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1.
Int J Mol Sci ; 23(1)2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35008910

RESUMO

Osteosarcoma is a highly common malignant bone tumor. Its highly metastatic properties are the leading cause of mortality for cancer. Niclosamide, a salicylanilide derivative, is an oral antihelminthic drug of known anticancer potential. However, the effect of niclosamide on osteosarcoma cell migration, invasion and the mechanisms underlying have not been fully clarified. Therefore, this study investigated niclosamide's underlying pathways and antimetastatic effects on osteosarcoma. In this study, U2OS and HOS osteosarcoma cell lines were treated with niclosamide and then subjected to assays for determining cell migration ability. The results indicated that niclosamide, at concentrations of up to 200 nM, inhibited the migration and invasion of human osteosarcoma U2OS and HOS cells and repressed the transforming growth factor beta-induced protein (TGFBI) expression of U2OS cells, without cytotoxicity. After TGFBI knockdown occurred, cellular migration and invasion behaviors of U2OS cells were significantly reduced. Moreover, niclosamide significantly decreased the phosphorylation of ERK1/2 in U2OS cells and the combination treatment of the MEK inhibitor (U0126) and niclosamide resulted in the intensive inhibition of the TGFBI expression and the migratory ability in U2OS cells. Therefore, TGFBI derived from osteosarcoma cells via the ERK pathway contributed to cellular migration and invasion and niclosamide inhibited these processes. These findings indicate that niclosamide may be a powerful preventive agent against the development and metastasis of osteosarcoma.


Assuntos
Movimento Celular , Proteínas da Matriz Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Niclosamida/farmacologia , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Fator de Crescimento Transformador beta/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Invasividade Neoplásica
2.
Clin Exp Pharmacol Physiol ; 49(3): 380-390, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34767669

RESUMO

Despite recent advances in diagnosis and treatment, osteosarcoma remains as the most common bone cancer in children and is associated with poor prognosis. Growing evidence has supported dysregulation of threonine and tyrosine protein kinase (TTK) expression as a hallmark of multiple cancers, however, its function in osteosarcoma remains to be elucidated. In the present study, we found that TTK was frequently overexpressed in osteosarcoma and associated with increased tumour growth and progression. Moreover, using both in vitro and in vivo assays, we provided evidence that TTK level was regulated by a molecular chaperone, heat shock protein 90 (Hsp90). Hsp90 directly interacted with TTK and prevents proteasome-dependent TTK degradation, leading to the accumulation of TTK in osteosarcoma cells. Elevated TTK promoted cancer cell proliferation and survival by activating cell-cycle progression and inhibiting apoptosis. Consistently, depletion of TTK by Hsp90 inhibition induced cell-cycle arrest, generated aneuploidy and eventually resulted in apoptotic cancer cell death. Together, our study revealed an important Hsp90-TTK regulatory axis in osteosarcoma cells to promote cancer cell growth and survival. These findings expand our knowledge on osteosarcoma pathogenesis and offer novel therapeutic options for clinical practice.


Assuntos
Carcinogênese , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas de Choque Térmico HSP90/metabolismo , Osteossarcoma/enzimologia , Proteínas Tirosina Quinases/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Feminino , Regulação Enzimológica da Expressão Gênica/fisiologia , Proteínas de Choque Térmico HSP90/genética , Humanos , Camundongos , Neoplasias Experimentais , Osteossarcoma/genética , Osteossarcoma/metabolismo , Proteínas Tirosina Quinases/genética
3.
Cells ; 10(12)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34944050

RESUMO

Tumorigenesis is a long-term and multistage process that often leads to the formation of metastases. During this pathological course, two major events appear to be crucial: primary tumour growth and metastatic expansion. In this context, despite research and clinical advances during the past decades, bone cancers remain a leading cause of death worldwide among paediatric cancer patients. Osteosarcomas are the most common malignant bone tumours in children and adolescents. Notwithstanding advances in therapeutic treatments, many patients succumb to these diseases. In particular, less than 30% of patients who demonstrate metastases at diagnosis or are poor responders to chemotherapy survive 5 years after initial diagnosis. LIM kinases (LIMKs), comprising LIMK1 and LIMK2, are common downstream effectors of several signalization pathways, and function as a signalling node that controls cytoskeleton dynamics through the phosphorylation of the cofilin family proteins. In recent decades, several reports have indicated that the functions of LIMKs are mainly implicated in the regulation of actin microfilament and the control of microtubule dynamics. Previous studies have thus identified LIMKs as cancer-promoting regulators in multiple organ cancers, such as breast cancer or prostate cancer. This review updates the current understanding of LIMK involvement in osteosarcoma progression.


Assuntos
Quinases Lim/metabolismo , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Animais , Neoplasias Ósseas/enzimologia , Remodelação Óssea , Humanos , Modelos Biológicos , Osteogênese
4.
Biochem Pharmacol ; 194: 114797, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34678225

RESUMO

In children and young adults, primary malignant bone tumours are mainly composed of osteosarcoma and Ewing's sarcoma. Despite advances in treatments, nearly 40% of patients succumb to these diseases. In particular, the clinical outcome of metastatic osteosarcoma or Ewing's sarcoma remains poor, with less than 30% of patients who develop metastases surviving five years after initial diagnosis. Over the last decade, the cancer research community has shown considerable interest in the processes of protein ubiquitination and deubiquitination. In particular, a growing number of studies show the relevance to target the ubiquitin-specific protease (USP) family in various cancers. This review provides an update on the current knowledge regarding the implication of these USPs in the progression of bone sarcoma: osteosarcoma and Ewing's sarcoma.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Sistemas de Liberação de Medicamentos/métodos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/enzimologia , Proteases Específicas de Ubiquitina/metabolismo , Antineoplásicos/administração & dosagem , Criança , Sistemas de Liberação de Medicamentos/tendências , Humanos , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo , Proteases Específicas de Ubiquitina/antagonistas & inibidores , Ubiquitinação/efeitos dos fármacos , Ubiquitinação/fisiologia
5.
Cells ; 10(9)2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34571917

RESUMO

Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the role of Ubiquitin-Specific Proteases (USPs) in the development of many cancers, few data exist regarding OS. In this context, RNA-sequencing analysis of OS cells and mesenchymal stem cells differentiated or not differentiated into osteoblasts reveals increased expression of four USPs in OS tumor cells: USP6, USP27x, USP41 and USP43. Tissue microarray analysis of patient biopsies demonstrates the nucleic and/or cytoplasmic expression of these four USPs at the protein level. Interestingly, Kaplan-Meyer analysis shows that the expression of two USPs, USP6 and USP41, is correlated with patient survival. In vivo experiments using a preclinical OS model, finally demonstrate that PR619, a USP inhibitor able to enhance protein ubiquitination in OS cell lines, reduces primary OS tumor growth and the development of lung metastases. In this context, in vitro experiments show that PR619 decreases the viability of OS cells, mainly by inducing a caspase3/7-dependent cell apoptosis. Overall, these results demonstrate the relevance of targeting USPs in OS.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Osteossarcoma/tratamento farmacológico , Inibidores de Proteases/farmacologia , Proteases Específicas de Ubiquitina/antagonistas & inibidores , Animais , Apoptose , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/secundário , Camundongos , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Prognóstico , Células Tumorais Cultivadas , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Gene ; 802: 145865, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352301

RESUMO

Osteosarcoma is a bone tumor that mainly affects children and adolescents. Interferons (IFNs) have been shown to exert antitumor effects in osteosarcoma cells, although the molecular mechanisms have not been fully realized. We investigated IFN-γ actions on osteosarcoma cells. Our results show that IFN-γ induces the accumulation of autophagosomes in osteosarcoma cells. IFN-γ treatment leads to the conversion of autophagy marker light chain 3 (LC3)-I to LC3-II in osteosarcoma cells, and this conversion is accompanied by puncta formation. Also, IFN-γ-mediated induction of autophagosome formation and autophagic flux require RNA-dependent protein kinase (PKR) activity. In addition, our findings show that IFN-γ-mediated osteosarcoma cell death is not dependent on PKR. Our study suggests that IFN-γ has differential effects that lead to induction of cell death and autophagy in osteosarcoma cells. Further evaluation of the IFN-γ-mediated molecular mechanism could lead to improved understanding of and targeted treatment strategies for osteosarcoma.


Assuntos
Autofagia , Neoplasias Ósseas/enzimologia , Interferon gama/metabolismo , Osteossarcoma/enzimologia , eIF-2 Quinase/metabolismo , Proteína 7 Relacionada à Autofagia/metabolismo , Neoplasias Ósseas/metabolismo , Osteossarcoma/metabolismo , Células Tumorais Cultivadas
7.
Endocr J ; 68(9): 1109-1116, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34121038

RESUMO

Gamma-glutamylcyclotransferase (GGCT) can promote the progression of osteosarcoma (OS). MicroRNAs also play significant roles in regulating the progression of OS. This study was designed to investigate whether miR-877 exerts its function in OS by targeting GGCT. The proliferation of OS cells (Saos-2 and U2OS) was detected by MTT and colony formation assays. The migration and invasion of OS cells were detected by transwell assays. The expressions of miRNAs and GGCT were detected by quantitative real-time PCR and Western blot. The luciferase reporter assay was performed to assess whether miR-877 could target GGCT. miR-877 was down-regulated both in OS tissues and OS cell lines (Saos-2 and U2OS). The overexpression of miR-877 inhibited the proliferation, migration, and invasion of OS cell lines, while the knockdown of miR-877 could negate effects. The expression of GGCT was increased in Saos-2 and U2OS cells. miR-877 could target GGCT, and the mRNA level of GGCT in Saos-2 and U2OS cells was decreased by the overexpression of miR-877. miR-877 overexpression inhibited the migration and invasion and suppressed the proliferation of Saos-2 and U2OS cells, and the overexpression of GGCT reversed this effects. The knockdown of miR-877 promoted the migration and invasion and facilitated the proliferation of Saos-2 and U2OS cells, and the silence of GGCT abolished this effects. Our findings suggested that miR-877 could inhibit the proliferation, migration, and invasion of OS cells by targeting GGCT.


Assuntos
MicroRNAs/fisiologia , Osteossarcoma/enzimologia , Osteossarcoma/patologia , gama-Glutamilciclotransferase/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo , Expressão Gênica , Humanos , MicroRNAs/genética , Invasividade Neoplásica/fisiopatologia , Osteossarcoma/genética , gama-Glutamilciclotransferase/genética
8.
Cells ; 10(5)2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069999

RESUMO

Osteosarcoma is the most common primary tumor of the bones affecting mainly young adults. Despite the advances in the field of systemic anticancer therapy, the prognosis of relapsed of metastatic osteosarcoma patients remain dismal with very short survival. However, the better understanding of the pathophysiology of this subtype of sarcoma has led to the identification of new targeted agents with significant activity. In fact, increased angiogenesis plays a major role in the tumor growth and survival of osteosarcoma patients. Several targeted agents have demonstrated a significant anti-tumor activity including multi-kinase inhibitors. In this review, we will discuss the pathophysiology, rationale, and role of targeting angiogenesis via the VEGF pathway in patients with osteosarcoma with emphasis on the published clinical trials and future directions.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neovascularização Patológica , Osteossarcoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/efeitos adversos , Animais , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Humanos , Terapia de Alvo Molecular , Osteossarcoma/enzimologia , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Transdução de Sinais , Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Biosci Rep ; 41(7)2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-33969873

RESUMO

AIM: Typical features of human osteosarcoma are highly invasive and migratory capacities. Our study aimed to investigate the roles of glycogen synthase kinase 3ß (GSK3ß) in human osteosarcoma metastasis. METHODS: GSK3ß expressions in clinical osteosarcoma tissues with or without metastasis were examined by immunohistochemical staining. The expressions of GSK3ß, p-GSK3ßSer9, and p-GSK3ßTyr216 in human osteoblast cells (hFOB1.19) and human osteosarcoma cells (MG63, SaOS-2, and U2-OS) were detected by Western blotting. The GSK3ß activity was measured by non-radio isotopic in vitro kinase assay. Migration and invasion abilities of MG-63 cells treated with small-molecular GSK3ß inhibitors were respectively examined by monolayer-based wound-healing assay and transwell assay. The mRNA expressions of GSK3ß, matrix metalloproteinase-2 (MMP-2), MMP-9, phosphatase with tensin homology (PTEN), and focal adhesion kinase (FAK) were detected after siRNA transfection for 72 h. Meanwhile, protein expressions of GSK3ß, FAK, p-FAKY397, PTEN, MMP-2, and MMP-9 were measured by Western blotting. RESULTS: Clinical osteosarcoma tissues with metastasis showed higher GSK3ß expressions. MG63 and U2-OS cells that were easy to occur metastasis showed significantly higher expressions and activities of GSK3ß than SaOS-2 cells. Inhibition of GSK3ß with small-molecular GSK3ß inhibitors in MG63 cells significantly attenuated cell migration and invasion. These effects were associated with reduced expressions of MMP-2 and MMP-9. Moreover, increased PTEN and decreased p-FAKY397 expressions were observed following GSK3ß knockdown by siRNA transfection. CONCLUSION: GSK3ß might promote osteosarcoma invasion and migration via pathways associated with PTEN and phosphorylation of FAK.


Assuntos
Neoplasias Ósseas/enzimologia , Movimento Celular , Quinase 1 de Adesão Focal/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Osteossarcoma/enzimologia , PTEN Fosfo-Hidrolase/metabolismo , Antineoplásicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Quinase 1 de Adesão Focal/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/genética , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/patologia , PTEN Fosfo-Hidrolase/genética , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais
10.
Cells ; 10(2)2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572933

RESUMO

4-Hydroxynonenal (HNE) is a major aldehydic product of lipid peroxidation known to exert several biological effects. Normal and malignant cells of the same origin express different sensitivity to HNE. We used human osteosarcoma cells (HOS) in different stages of differentiation in vitro, showing differences in mitosis, DNA synthesis, and alkaline phosphatase (ALP) staining. Differentiated HOS cells showed decreased proliferation (3H-thymidine incorporation), decreased viability (thiazolyl blue tetrazolium bromide-MTT), and increased apoptosis and necrosis (nuclear morphology by staining with 4',6-diamidino-2-phenylindole-DAPI). Differentiated HOS also had less expressed c-MYC, but the same amount of c-FOS (immunocytochemistry). When exposed to HNE, differentiated HOS produced more reactive oxygen species (ROS) in comparison with undifferentiated HOS. To clarify this, we measured HNE metabolism by an HPLC method, total glutathione (GSH), oxidized GSH (ox GSH), glutathione transferase activity (GST), proteasomal activity by enzymatic methods, HNE-protein adducts by genuine ELISA and fatty acid composition by GC-MS in these cell cultures. Differentiated HOS cells had less GSH, lower HNE metabolism, increased formation of HNE-protein adducts, and lower proteasomal activity, in comparison to undifferentiated counterpart cells, while GST and oxGSH were the same. Fatty acids analyzed by GC-MS showed that there is an increase in C20:3 in differentiated HOS while the amount of C20:4 remained the same. The results showed that the cellular machinery responsible for protection against toxicity of HNE was less efficient in differentiated HOS cells. Moreover, differentiated HOS cells contained more C20:3 fatty acid, which might make them more sensitive to free radical-initiated oxidative chain reactions and more vulnerable to the effects of reactive aldehydes such as HNE. We propose that HNE might act as natural promotor of decay of malignant (osteosarcoma) cells in case of their differentiation associated with alteration of the lipid metabolism.


Assuntos
Aldeídos/farmacologia , Diferenciação Celular , Peroxidação de Lipídeos , Osteossarcoma/patologia , Fosfatase Alcalina/metabolismo , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Humanos , Necrose , Osteossarcoma/enzimologia , Complexo de Endopeptidases do Proteassoma/metabolismo
11.
J Clin Pathol ; 74(5): 321-326, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33589531

RESUMO

AIMS: Osteosarcoma (OS) is the most common primary malignant tumour of the bone. However, further improvement in survival has not been achieved due to a lack of well-validated prognostic markers and more effective therapeutic agents. Recently, the c-Myc-phosphoribosyl pyrophosphate synthetase 2 (PRPS2) pathway has been shown to promote nucleic acid metabolism and cancer cell proliferation in malignant melanoma; phosphorylated mammalian target of rapamycin (p-mTOR) has been upregulated and an effective therapeutic target in OS. However, the p-mTOR-PRPS2 pathway has not been evaluated in OS. METHODS: In this study, the expression level of PRPS2, p-mTOR and marker of proliferation (MKI-67) was observed in a cohort of specimens (including 236 OS cases and 56 control samples) using immunohistochemistry, and the association between expression level and clinicopathological characteristics of patients with OS was analysed. RESULTS: PRPS2 protein level, which is related to tumour proliferation, was higher in OS cells (p=0.003) than in fibrous dysplasia, and the higher PRPS2 protein level was associated with a higher tumour recurrence (p=0.001). In addition, our statistical analysis confirmed that PRPS2 is a novel, independent prognostic indicator of OS. Finally, we found that the expression of p-mTOR was associated with the poor prognosis of patients with OS (p<0.05). CONCLUSIONS: PRPS2 is an independent prognostic marker and a potential therapeutic target for OS.


Assuntos
Neoplasias Ósseas/enzimologia , Neoplasias Femorais/enzimologia , Osteossarcoma/enzimologia , Ribose-Fosfato Pirofosfoquinase/análise , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/cirurgia , Proliferação de Células , Criança , Pré-Escolar , Feminino , Neoplasias Femorais/mortalidade , Neoplasias Femorais/patologia , Neoplasias Femorais/cirurgia , Humanos , Imuno-Histoquímica , Lactente , Antígeno Ki-67/análise , Masculino , Recidiva Local de Neoplasia , Osteossarcoma/mortalidade , Osteossarcoma/patologia , Osteossarcoma/cirurgia , Fosforilação , Serina-Treonina Quinases TOR/análise , Análise Serial de Tecidos , Resultado do Tratamento
12.
Biomed Pharmacother ; 136: 111202, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33453607

RESUMO

PURPOSE: EF24, a synthetic analogue of curcumin, was developed as an anti-tumor compound to induce apoptosis, inhibit proliferation and metastasis in various cancers. However, whether EF24 induces ferroptosis in osteosarcoma cells or not, and its underlying mechanism remains largely elusive. METHODS: After EF24 combining with or without other compounds treatments, mRNA expression profiles were proceeded by RNA sequencing. Cytotoxicity was measured by cell counting kit-8 assay. Cell death was quantified by flow cytometer. Gene expression was quantified by real-time PCR. Protein level was detected by western blot. Malonydialdehyde (MDA) level was measured by lipid peroxidation MDA assay kit. Reactive oxygen species (ROS) level was measured by ROS Assay Kit. Ferric ion was measured by Iron Assay kit. RESULTS: EF24 significantly induced cell death in osteosarcoma cell lines, and this effect was significantly reversed by ferrostatin-1, but not Z-VAD(Ome)-FMK, MRT68921 or necrosulfonamide. EF24 significantly increased MDA level, ROS level and intracellular ferric ion level, these effects were significantly attenuated by ferrostatin-1. EF24 upregulated HMOX1 expression in a dose dependent manner, overexpression of HMOX1 facilitated EF24 to induce ferroptosis in osteosarcoma cell lines. HMOX1 knockdown attenuated EF24-induced cytotoxicity and attenuated EF24-induced inhibition of Glutathione Peroxidase 4 (GPX4) expression. CONCLUSION: Our results showed that EF24 upregulated HMOX1 to suppress GPX4 expression to induce ferroptosis by increasing MDA level, ROS level and intracellular ferric ion level. Thus, EF24 might serve as a potential agent for the treatment of HMOX1-positive osteosarcoma patients.


Assuntos
Antineoplásicos/farmacologia , Compostos de Benzilideno/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Ferroptose/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Osteossarcoma/tratamento farmacológico , Piperidonas/farmacologia , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Heme Oxigenase-1/genética , Humanos , Ferro/metabolismo , Malondialdeído/metabolismo , Osteossarcoma/enzimologia , Osteossarcoma/genética , Osteossarcoma/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
13.
Signal Transduct Target Ther ; 6(1): 25, 2021 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-33468990

RESUMO

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Although activator of HSP90 ATPase activity 1 (AHA1) is reported to be a potential oncogene, its role in osteosarcoma progression remains largely unclear. Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis, the relationship between AHA1 and cancer metabolism is unknown. In this study, we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients. AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo. Mechanistically, AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma. Notably, we identified that isocitrate dehydrogenase 1 (IDH1) is a novel client protein of Hsp90-AHA1. Furthermore, the IDH1 protein level was positively correlated with AHA1 in osteosarcoma. And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma. Moreover, high IDH1 level was also associated with poor prognosis of osteosarcoma patients. This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis, which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.


Assuntos
Neoplasias Ósseas/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Isocitrato Desidrogenase/biossíntese , Chaperonas Moleculares/biossíntese , Proteínas de Neoplasias/metabolismo , Osteossarcoma/enzimologia , Regulação para Cima , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Isocitrato Desidrogenase/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Chaperonas Moleculares/genética , Proteínas de Neoplasias/genética , Osteossarcoma/genética , Osteossarcoma/patologia
14.
Biomed Pharmacother ; 134: 111155, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33370628

RESUMO

Osteosarcoma (OS) is the most common type of bone malignant tumors. Clinical commonly used therapeutic drugs of OS treatment are prone to toxic and side effects, so it is very urgent to develop new drugs with low toxicity and low side effects. As a Chinese herbal medicine, Cardamonin (CAR) (C16H14O4) has inhibitory effects in various tumors. In the present study, we investigated the effects of CAR on OS cells in vitro and in vivo. We found that CAR inhibited cell proliferation, reduced migration, decreased invasion, and induced G2 / M arrest of OS cells. Notably, we demonstrated that CAR had no obvious effect on proliferation and apoptosis of normal cells. Besides, CAR repressed tumor growth of OS cells in xenograft mouse model. Mechanically, we found that CAR increased the phosphorylation level of P38 and JNK. In summary, our research validates that CAR may inhibit the proliferation, migration, and invasion of OS and promote apoptosis possibly by activating P38 and JNK Mitogen-activated protein kinase (MAPK) signaling pathway.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Chalconas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Osteossarcoma/tratamento farmacológico , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ativação Enzimática , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Fosforilação , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
15.
J Cell Physiol ; 236(3): 1606-1615, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32697358

RESUMO

Osteosarcoma (OS) is a primary malignant bone tumour which usually occurs in children and adolescents. OS is primarily a result of chromosomal aberrations, a combination of acquired genetic changes and, hereditary, resulting in the dysregulation of cellular functions. The Hippo signalling pathway regulates cell and tissue growth by modulating cell proliferation, differentiation, and migration in developing organs. Mammalian STE20-like 1/2 (MST1/2) protein kinases are activated by neurofibromatosis type 2, Ras association domain family member 2, kidney and brain protein, or other factors. Interactions between MST1/2 and salvador family WW domain-containing protein 1 activate large tumour suppressor kinase 1/2 proteins, which in turn phosphorylate the downstream Yes-associated protein 1/transcriptional coactivator with PDZ-binding motif (YAP/TAZ). Moreover, dysregulation of this pathway can lead to aberrant cell growth, resulting in tumorigenesis. Interestingly, small molecules targeting the Hippo signalling pathways, through affecting YAP/TAZ cellular localisation and their interaction with members of the TEA/ATTS domain family of transcriptional enhancers are being developed and hold promise for the treatment of OS. This review discusses the existing knowledge about the involvement of the Hippo signalling cascade in OS and highlights several small molecule inhibitors as potential novel therapeutics.


Assuntos
Osteossarcoma/enzimologia , Osteossarcoma/terapia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Animais , Modelos Biológicos , Terapia de Alvo Molecular , Osteossarcoma/patologia
16.
Biosci Rep ; 41(1)2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33289496

RESUMO

Drug repurposing is a cost-effective means of targeting new therapies for cancer. We have examined the effects of the repurposed drugs, bezafibrate, medroxyprogesterone acetate and valproic acid on human osteosarcoma cells, i.e., SAOS2 and MG63 compared with their normal cell counterparts, i.e. mesenchymal stem/stromal cells (MSCs). Cell growth, viability and migration were measured by biochemical assay and live cell imaging, whilst levels of lipid-synthesising enzymes were measured by immunoblotting cell extracts. These drug treatments inhibited the growth and survival of SAOS2 and MG63 cells most effectively when used in combination (termed V-BAP). In contrast, V-BAP treated MSCs remained viable with only moderately reduced cell proliferation. V-BAP treatment also inhibited migratory cell phenotypes. MG63 and SAOS2 cells expressed much greater levels of fatty acid synthase and stearoyl CoA desaturase 1 than MSCs, but these elevated enzyme levels significantly decreased in the V-BAP treated osteosarcoma cells prior to cell death. Hence, we have identified a repurposed drug combination that selectively inhibits the growth and survival of human osteosarcoma cells in association with altered lipid metabolism without adversely affecting their non-transformed cell counterparts.


Assuntos
Bezafibrato/administração & dosagem , Neoplasias Ósseas/patologia , Proliferação de Células/efeitos dos fármacos , Acetato de Medroxiprogesterona/administração & dosagem , Células-Tronco Mesenquimais/efeitos dos fármacos , Osteossarcoma/patologia , Ácido Valproico/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/enzimologia , Linhagem Celular Tumoral , Regulação para Baixo , Reposicionamento de Medicamentos , Quimioterapia Combinada , Ácido Graxo Sintases/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/enzimologia , Estearoil-CoA Dessaturase/metabolismo , Regulação para Cima
17.
Med Sci Monit ; 26: e927837, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33284788

RESUMO

BACKGROUND Osteosarcoma (OS) is very common worldwide, and the mechanisms underlying its development remain unclear. This study aims to identify key genes promoting the reproduction, invasion, and transfer of osteosarcoma cells. MATERIAL AND METHODS Gene expression profile data (GSE42352 and GSE42572) were downloaded from the Gene Expression Omnibus database. Differentially expressed genes were calculated using R software. Gene ontology and enriched pathway analysis of mRNAs were analyzed by using FunRich. Verification of the genes was conducted by using quantitative real-time polymerase chain reaction and western blot analyses to measure gene expression. Transwell and wound-healing assays were performed on osteosarcoma cells after knockdown to detect whether the genes enhanced the aggressiveness of osteosarcoma. RESULTS In total, 34 genes were selected after filtering. Kyoto Encyclopedia of Genes and Genomes enrichment analysis demonstrated that the genes were enriched in multiple tumor pathways. N-acetylgalactosaminyltransferase 1 (GALNT1) was identified for further study, and its expression was higher in osteosarcoma cells than in human osteoblasts. The invasion ability of cells was significantly decreased after gene knockdown. CONCLUSIONS Through the use of microarray and bioinformatics analysis, differentially expressed genes were selected and a complete gene network was constructed. Our findings provide new biomarkers for the treatment and prognosis of osteosarcoma. These biomarkers may contribute to the discovery of new therapeutic targets for clinical application.


Assuntos
Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Regulação Neoplásica da Expressão Gênica , N-Acetilgalactosaminiltransferases/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Neoplasias Ósseas/enzimologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Perfilação da Expressão Gênica , Humanos , N-Acetilgalactosaminiltransferases/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Osteossarcoma/enzimologia , Mapeamento de Interação de Proteínas , Cicatrização , Polipeptídeo N-Acetilgalactosaminiltransferase
18.
Histol Histopathol ; 35(12): 1511-1520, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33372687

RESUMO

AIMS: To investigate the effects and the mechanisms of action of Diallyl trisulfide (DATS) on the proliferation and metastasis of human osteosarcoma (OS) U2OS. METHODS: U2OS cells were treated by different concentrations of DATS at different time points. Cell proliferations were measured by MTT assay. DATS induced cell cycle distribution and apoptosis were evaluated by flow cytometry (FCM) with Annexin-V. Cell migration and invasion were detected by wound healing assay and transwell assay. The effects of DATS in U2OS cell growth and metastasis were also detected in a mouse OS xenograft model. RESULTS: A time- and concentration-dependent cytotoxic effect of DATS was observed in U2OS cells. FCM with PI staining and Annexin-V -FITC indicated that DATS induces apoptosis and a G0/G1 cell cycle arrest of U2OS cells at all concentrations from 25 µmol/l to 100 µmol/l. DATS also inhibits the migration and invasion of U2OS cells. Western blot showed that the expression levels of p-AKT, p-GSK3ß, Bcl-2, Vimentin and ß-catenin were decreased, while the expression levels of Bad, Bax and E-cadherin were significantly increased in DATS treated U2OS cells. Analysis using a mouse xenograft model indicated that xenografts of DATS treatment group had a significant decrease in tumor volume and weight compared to the control group. Lung metastasis models in mice demonstrated that treatment of DATS inhibits lung metastasis of OS in vivo. CONCLUSIONS: These data suggested that DATS inhibits OS development and progression through the regulation of PI3K/AKT/GSK3ß signaling pathways, accompanied by downregulation of Bcl-2, Vimentin and ß-catenin, as well as upregulation of Bad, Bax and E-cadherin. Therefore, our data demonstrated that DATS exerted its anticancer effects by inhibiting cell proliferation, migration and invasion in vitro and in vivo. These results provide evidence for the use of the natural product DATS either alone or in combination with standard therapy for OS.


Assuntos
Compostos Alílicos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Osteossarcoma/tratamento farmacológico , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sulfetos/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Cell Mol Med ; 24(20): 11960-11971, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32914567

RESUMO

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and adolescents. The long-term survival rate of OS patients is stubbornly low mainly due to the chemotherapy resistance. We therefore aimed to investigate the antitumoral effects and underlying mechanisms of proanthocyanidin B2 (PB2) on OS cells in the current study. The effect of PB2 on the proliferation and apoptosis of OS cell lines was assessed by CCK-8, colony formation, and flow cytometry assays. The target gene and protein expression levels were measured by qRT-PCR and Western blotting. A xenograft mouse model was established to assess the effects of PB2 on OS proliferation and apoptosis in vivo. Results from in vitro experiments showed that PB2 inhibited the proliferation and induced apoptosis of OS cells, and also increased the expression levels of apoptosis-related proteins. Moreover, PB2 induced OS cell apoptosis through suppressing the PI3K/AKT signalling pathway. The in vivo experiments further confirmed that PB2 could inhibit OS tumour growth and induce its apoptosis. Taken together, these results suggested that PB2 inhibited the proliferation and induced apoptosis of OS cells through the suppression of the PI3K/AKT signalling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Osteossarcoma/enzimologia , Osteossarcoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proantocianidinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Permeabilidade , Fosfotirosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Signal Transduct Target Ther ; 5(1): 201, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929074

RESUMO

Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4+ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.


Assuntos
Neoplasias Ósseas , Proteína 1 Semelhante à Quitinase-3 , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias , Osteossarcoma , Animais , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/genética , Proteína 1 Semelhante à Quitinase-3/biossíntese , Proteína 1 Semelhante à Quitinase-3/genética , Humanos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Especificidade de Órgãos , Osteossarcoma/enzimologia , Osteossarcoma/genética
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