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1.
Mol Cancer ; 22(1): 4, 2023 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-36624516

RESUMO

BACKGROUND: Metastatic colonization is one of the critical steps in tumor metastasis. A pre-metastatic niche is required for metastatic colonization and is determined by tumor-stroma interactions, yet the mechanistic underpinnings remain incompletely understood. METHODS: PCR-based miRNome profiling, qPCR, immunofluorescent analyses evaluated the expression of exosomal miR-141 and cell-to-cell communication. LC-MS/MS proteomic profiling and Dual-Luciferase analyses identified YAP1 as the direct target of miR-141. Human cytokine profiling, ChIP, luciferase reporter assays, and subcellular fractionation analyses confirmed YAP1 in modulating GROα production. A series of in vitro tumorigenic assays, an ex vivo model and Yap1 stromal conditional knockout (cKO) mouse model demonstrated the roles of miR-141/YAP1/GROα/CXCR1/2 signaling cascade. RNAi, CRISPR/Cas9 and CRISPRi systems were used for gene silencing. Blood sera, OvCa tumor tissue samples, and tissue array were included for clinical correlations. RESULTS: Hsa-miR-141-3p (miR-141), an exosomal miRNA, is highly secreted by ovarian cancer cells and reprograms stromal fibroblasts into proinflammatory cancer-associated fibroblasts (CAFs), facilitating metastatic colonization. A mechanistic study showed that miR-141 targeted YAP1, a critical effector of the Hippo pathway, reducing the nuclear YAP1/TAZ ratio and enhancing GROα production from stromal fibroblasts. Stromal-specific knockout (cKO) of Yap1 in murine models shaped the GROα-enriched microenvironment, facilitating in vivo tumor colonization, but this effect was reversed after Cxcr1/2 depletion in OvCa cells. The YAP1/GROα correlation was demonstrated in clinical samples, highlighting the clinical relevance of this research and providing a potential therapeutic intervention for impeding premetastatic niche formation and metastatic progression of ovarian cancers. CONCLUSIONS: This study uncovers miR-141 as an OvCa-derived exosomal microRNA mediating the tumor-stroma interactions and the formation of tumor-promoting stromal niche through activating YAP1/GROα/CXCRs signaling cascade, providing new insight into therapy for OvCa patients with peritoneal metastases.


Assuntos
MicroRNAs , Neoplasias Ovarianas , Humanos , Animais , Camundongos , Feminino , Cromatografia Líquida , Proteômica , Espectrometria de Massas em Tandem , Neoplasias Ovarianas/genética , MicroRNAs/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Microambiente Tumoral
2.
Int J Mol Sci ; 23(23)2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36499591

RESUMO

Ovarian cancer is one of the most lethal gynecological cancers worldwide. The poor prognosis of this malignancy is substantially attributed to the inadequate symptomatic biomarkers for early diagnosis and effective remedies to cure the disease against chemoresistance and metastasis. Ovarian cancer metastasis is often relatively passive, and the single clusters of ovarian cancer cells detached from the primary ovarian tumor are transcoelomic spread by the peritoneal fluid throughout the peritoneum cavity and omentum. Our earlier studies revealed that lipid-enriched ascitic/omental microenvironment enforced metastatic ovarian cancer cells to undertake metabolic reprogramming and utilize free fatty acids as the main energy source for tumor progression and aggression. Intriguingly, cell susceptibility to ferroptosis has been tightly correlated with the dysregulated fatty acid metabolism (FAM), and enhanced iron uptake as the prominent features of ferroptosis are attributed to the strengthened lipid peroxidation and aberrant iron accumulation, suggesting that ferroptosis induction is a targetable vulnerability to prevent cancer metastasis. Therefore, the standpoints about tackling altered FAM in combination with ferroptosis initiation as a dual-targeted therapy against advanced ovarian cancer were highlighted herein. Furthermore, a discussion on the prospect and challenge of inducing ferroptosis as an innovative therapeutic approach for reversing remedial resistance in cancer interventions was included. It is hoped this proof-of-concept review will indicate appropriate directions for speeding up the translational application of ferroptosis-inducing compounds (FINs) to improve the efficacy of ovarian cancer treatment.


Assuntos
Ferroptose , Neoplasias Ovarianas , Neoplasias Peritoneais , Feminino , Humanos , Metabolismo dos Lipídeos , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Omento , Microambiente Tumoral
3.
Int J Mol Sci ; 23(12)2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35743298

RESUMO

Ovarian cancer is one of the most lethal gynecological malignancies worldwide, and chemoresistance is a critical obstacle in the clinical management of the disease. Recent studies have suggested that exploiting cancer cell metabolism by applying AMP-activated protein kinase (AMPK)-activating agents and distinctive adjuvant targeted therapies can be a plausible alternative approach in cancer treatment. Therefore, the perspectives about the combination of AMPK activators together with VEGF/PD-1 blockade as a dual-targeted therapy against ovarian cancer were discussed herein. Additionally, ferroptosis, a non-apoptotic regulated cell death triggered by the availability of redox-active iron, have been proposed to be governed by multiple layers of metabolic signalings and can be synergized with immunotherapies. To this end, ferroptosis initiating therapies (FITs) and metabolic rewiring and immunotherapeutic approaches may have substantial clinical potential in combating ovarian cancer development and progression. It is hoped that the viewpoints deliberated in this review would accelerate the translation of remedial concepts into clinical trials and improve the effectiveness of ovarian cancer treatment.


Assuntos
Proteínas Quinases Ativadas por AMP , Neoplasias Ovarianas , Proteínas Quinases Ativadas por AMP/metabolismo , Carcinoma Epitelial do Ovário , Feminino , Humanos , Lipídeos/uso terapêutico , Neoplasias Ovarianas/patologia , Receptor de Morte Celular Programada 1 , Fator A de Crescimento do Endotélio Vascular/uso terapêutico
4.
Cancers (Basel) ; 13(19)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34638280

RESUMO

Peritoneal metastases are frequently found in high-grade serous carcinoma (HGSOC) patients and are commonly associated with a poor prognosis. The tumor microenvironment (TME) is a complex milieu that plays a critical role in epigenetic alterations driving tumor development and metastatic progression. However, the impact of epigenetic alterations on metastatic ovarian cancer cells in the harsh peritoneal microenvironment remains incompletely understood. Here, we identified that miR-33b is frequently silenced by promoter hypermethylation in HGSOC cells derived from metastatic omental tumor tissues. Enforced expression of miR-33b abrogates the oncogenic properties of ovarian cancer cells cocultured in omental conditioned medium (OCM), which mimics the ascites microenvironment, and in vivo tumor growth. Of note, restoration of miR-33b inhibited OCM-upregulated de novo lipogenesis and fatty acid ß-oxidation in ovarian cancer cells, indicating that miR-33b may play a novel tumor suppressor role in the lipid-mediated oncogenic properties of metastatic ovarian cancer cells found in the omentum. Mechanistic studies demonstrated that miR-33b directly targets transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing the activities of fatty acid synthase (FASN) and carnitine palmitoyltransferase 1A (CPT1A) in modulating lipid metabolic activities and simultaneously inhibiting the phosphorylation of NF-κB signaling to govern the oncogenic behaviors of ovarian cancer cells. Thus, our data suggest that a lipid-rich microenvironment may cause epigenetic silencing of miR-33b, which negatively modulates ovarian cancer peritoneal metastases, at least in part, by suppressing TAK1/FASN/CPT1A/NF-κB signaling.

5.
Cancers (Basel) ; 13(18)2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34572804

RESUMO

Emerging evidence indicates that hypoxia plays a critical role in governing the transcoelomic metastasis of ovarian cancer. Hence, targeting hypoxia may be a promising approach to prevent the metastasis of ovarian cancer. Here, we report that BCL2A1, a BCL2 family member, acts as a hypoxia-inducible gene for promoting tumor progression in ovarian cancer peritoneal metastases. We demonstrated that BCL2A1 was induced not only by hypoxia but also other physiological stresses through NF-κB signaling and then was gradually reduced by the ubiquitin-proteasome pathway in ascites-derived ovarian cancer cells. The upregulated BCL2A1 was frequently found in advanced metastatic ovarian cancer cells, suggesting its clinical relevance in ovarian cancer metastatic progression. Functionally, BCL2A1 enhanced the foci formation ability of ovarian cancer cells in a stress-conditioned medium, colony formation in an ex vivo omental tumor model, and tumor dissemination in vivo. Under stress conditions, BCL2A1 accumulated and colocalized with mitochondria to suppress intrinsic cell apoptosis by interacting with the BH3-only subfamily BCL2 members HRK/BAD/BID in ovarian cancer cells. These findings indicate that BCL2A1 is an early response factor that maintains the survival of ovarian cancer cells in the harsh tumor microenvironment.

7.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207286

RESUMO

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's "Seed and Soil" hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor ß (TGFß), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.


Assuntos
Neoplasias/patologia , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Animais , Diferenciação Celular , Humanos , Imunoterapia/métodos , Metástase Neoplásica , Neoplasias/imunologia , Neoplasias/terapia , Macrófagos Associados a Tumor/patologia
8.
Clin Epigenetics ; 13(1): 142, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294135

RESUMO

BACKGROUND: In contrast to stable genetic events, epigenetic changes are highly plastic and play crucial roles in tumor evolution and development. Epithelial ovarian cancer (EOC) is a highly heterogeneous disease that is generally associated with poor prognosis and treatment failure. Profiling epigenome-wide DNA methylation status is therefore essential to better characterize the impact of epigenetic alterations on the heterogeneity of EOC. METHODS: An epigenome-wide association study was conducted to evaluate global DNA methylation in a retrospective cohort of 80 mixed subtypes of primary ovarian cancers and 30 patients with high-grade serous ovarian carcinoma (HGSOC). Three demethylating agents, azacytidine, decitabine, and thioguanine, were tested their anti-cancer and anti-chemoresistant effects on HGSOC cells. RESULTS: Global DNA hypermethylation was significantly associated with high-grade tumors, platinum resistance, and poor prognosis. We determined that 9313 differentially methylated probes (DMPs) were enriched in their relative gene regions of 4938 genes involved in small GTPases and were significantly correlated with the PI3K-AKT, MAPK, RAS, and WNT oncogenic pathways. On the other hand, global DNA hypermethylation was preferentially associated with recurrent HGSOC. A total of 2969 DMPs corresponding to 1471 genes were involved in olfactory transduction, and calcium and cAMP signaling. Co-treatment with demethylating agents showed significant growth retardation in ovarian cancer cells through differential inductions, such as cell apoptosis by azacytidine or G2/M cell cycle arrest by decitabine and thioguanine. Notably, azacytidine and decitabine, though not thioguanine, synergistically enhanced cisplatin-mediated cytotoxicity in HGSOC cells. CONCLUSIONS: This study demonstrates the significant association of global hypermethylation with poor prognosis and drug resistance in high-grade EOC and highlights the potential of demethylating agents in cancer treatment.


Assuntos
Resistência a Medicamentos/genética , Epigenoma/genética , Neoplasias Ovarianas/genética , Metilação de DNA/efeitos dos fármacos , Resistência a Medicamentos/fisiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos
9.
Cell Death Dis ; 12(4): 341, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795649

RESUMO

The JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.


Assuntos
Cisteína Endopeptidases/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Janus Quinase 2/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Platina/farmacologia , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Commun Biol ; 2: 281, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31372520

RESUMO

Ovarian cancer is an intra-abdominal tumor in which the presence of ascites facilitates metastatic dissemination, and associated with poor prognosis. However, the significance of metabolic alterations in ovarian cancer cells in the ascites microenvironment remains unclear. Here we show ovarian cancer cells exhibited increased aggressiveness in ascites microenvironment via reprogramming of lipid metabolism. High lipid metabolic activities are found in ovarian cancer cells when cultured in the ascites microenvironment, indicating a metabolic shift from aerobic glycolysis to ß-oxidation and lipogenesis. The reduced AMP-activated protein kinase (AMPK) activity due to the feedback effect of high energy production led to the activation of its downstream signaling, which in turn, enhanced the cancer growth. The combined treatment of low toxic AMPK activators, the transforming growth factor beta-activated kinase 1 (TAK1) and fatty acid synthase (FASN) inhibitors synergistically impair oncogenic augmentation of ovarian cancer. Collectively, targeting lipid metabolism signaling axis impede ovarian cancer peritoneal metastases.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/prevenção & controle , Neoplasias Peritoneais/secundário , Feminino , Humanos , Microambiente Tumoral
11.
Clin Cancer Res ; 25(19): 5947-5960, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31285371

RESUMO

PURPOSE: Up to 80% of patients with ovarian cancer develop platinum resistance over time to platinum-based chemotherapy. Increased HIF1α level is an important mechanism governing platinum resistance in platinum-resistant ovarian cancer (PROC). However, the mechanism regulating HIF1α stability in PROC remains largely unknown. Here, we elucidate the mechanism of HIF1α stability regulation in PROC and explore therapeutic approaches to overcome cisplatin resistance in ovarian cancer. EXPERIMENTAL DESIGN: We first used a quantitative high-throughput combinational screen (qHTCS) to identify novel drugs that could resensitize PROC cells to cisplatin. Next, we evaluated the combination efficacy of inhibitors of HIF1α (YC-1), ERK (selumetinib), and TGFß1 (SB431542) with platinum drugs by in vitro and in vivo experiments. Moreover, a novel TGFß1/ERK/PHD2-mediated pathway regulating HIF1α stability in PROC was discovered. RESULTS: YC-1 and selumetinib resensitized PROC cells to cisplatin. Next, the prolyl hydroxylase domain-containing protein 2 (PHD2) was shown to be a direct substrate of ERK. Phosphorylation of PHD2 by ERK prevents its binding to HIF1α, thus inhibiting HIF1α hydroxylation and degradation-increasing HIF1α stability. Significantly, ERK/PHD2 signaling in PROC cells is dependent on TGFß1, promoting platinum resistance by stabilizing HIF1α. Inhibition of TGFß1 by SB431542, ERK by selumetinib, or HIF1α by YC-1 efficiently overcame platinum resistance both in vitro and in vivo. The results from clinical samples confirm activation of the ERK/PHD2/HIF1α axis in patients with PROC, correlating highly with poor prognoses for patients. CONCLUSIONS: HIF1α stabilization is regulated by TGFß1/ERK/PHD2 axis in PROC. Hence, inhibiting TGFß1, ERK, or HIF1α is potential strategy for treating patients with PROC.


Assuntos
Cisplatino/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína Quinase 1 Ativada por Mitógeno/genética , Neoplasias Ovarianas/genética , Fator de Crescimento Transformador beta1/genética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
PLoS One ; 13(10): e0198980, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30303958

RESUMO

Gastric cancer is the third most common cause of death from cancer in the world and it remains difficult to cure in Western countries, primarily because most patients present with advanced disease. Currently, CEA, CA50 and CA72-4 are commonly used as tumor markers for gastric cancer by immunoassays. However, the drawback and conundrum of immunoassay are the unceasing problem in standardization of quality of antibodies and time/effort for the intensive production. Therefore, there is an urgent need for the development of a standardized assay to detect gastric cancer at the early stage. Aptamers are DNA or RNA oligonucleotides with structural domain which recognize ligands such as proteins with superior affinity and specificity when compared to antibodies. In this study, SELEX (Systematic Evolution of Ligands by Exponential enrichment) technique was adopted to screen a random 30mer RNA library for aptamers targeting CEA, CA50 and CA72-4 respectively. Combined with high-throughput sequencing, we identified 6 aptamers which specifically target for these three biomarkers of gastrointestinal cancer. Intriguingly, the predicted secondary structures of RNA aptamers from each antigen showed significant structural similarity, suggesting the structural recognition between the aptamers and the antigens. Moreover, we determined the dissociation constants of all the aptamers to their corresponding antigens by fluorescence spectroscopy, which further demonstrated high affinities between the aptamers and the antigens. In addition, immunostaining of gastric adenocarcinoma cell line AGS using CEA Aptamer probe showed positive fluorescent signal which proves the potential of the aptamer as a detection tool for gastric cancer. Furthermore, substantially decreased cell viability and growth were observed when human colorectal cell line LS-174T was transfected with each individual aptamers. Taking together, these novel RNA aptamers targeting gastrointestinal cancer biomarker CEA, CA50 and CA72-4 will aid further development and standardization of clinical diagnostic method with better sensitivity and specificity, and potentially future therapeutics development of gastric cancer.


Assuntos
Antígenos Glicosídicos Associados a Tumores/análise , Aptâmeros de Nucleotídeos/química , Biomarcadores Tumorais/análise , Antígeno Carcinoembrionário/análise , Neoplasias Gastrointestinais/diagnóstico , Adenocarcinoma , Linhagem Celular Tumoral , Sobrevivência Celular , DNA/análise , Neoplasias Gastrointestinais/genética , Biblioteca Gênica , Células HeLa , Humanos , Prognóstico , RNA Neoplásico/análise , Técnica de Seleção de Aptâmeros , Sensibilidade e Especificidade
13.
Cancer Lett ; 428: 104-116, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29704517

RESUMO

The acquisition of resistance is a major obstacle to the clinical use of platinum drugs for ovarian cancer treatment. Increase of DNA damage response is one of major mechanisms contributing to platinum-resistance. However, how DNA damage response is regulated in platinum-resistant ovarian cancer cells remains unclear. Using quantitative high throughput combinational screen (qHTCS) and RNA-sequencing (RNA-seq), we show that dual oxidase maturation factor 1 (DUOXA1) is overexpressed in platinum-resistant ovarian cancer cells, resulting in over production of reactive oxygen species (ROS). Elevated ROS level sustains the activation of ATR-Chk1 pathway, leading to resistance to cisplatin in ovarian cancer cells. Moreover, using qHTCS we identified two Chk1 inhibitors (PF-477736 and AZD7762) that re-sensitize resistant cells to cisplatin. Blocking this novel pathway by inhibiting ROS, DUOXA1, ATR or Chk1 effectively overcomes cisplatin resistance in vitro and in vivo. Significantly, the clinical studies also confirm the activation of ATR and DOUXA1 in ovarian cancer patients, and elevated DOUXA1 or ATR-Chk1 pathway correlates with poor prognosis. Taken together, our findings not only reveal a novel mechanism regulating cisplatin resistance, but also provide multiple combinational strategies to overcome platinum-resistance in ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Benzodiazepinonas/farmacologia , Benzodiazepinonas/uso terapêutico , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/metabolismo , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Proteínas de Membrana/antagonistas & inibidores , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Oncogene ; 37(29): 3981-3997, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29662190

RESUMO

Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2-STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11-JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS-IL-11-JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.


Assuntos
Comunicação Autócrina/fisiologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Interleucina-11/metabolismo , Janus Quinase 2/metabolismo , Platina/farmacologia , Comunicação Autócrina/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Imidazóis/farmacologia , Imunoterapia/métodos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-fos/metabolismo , Pirazóis/farmacologia , Piridazinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Mol Cancer ; 16(1): 11, 2017 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-28095864

RESUMO

BACKGROUND: Cancer metastasis is determined by the formation of the metastatic niche and the ability of cancer cells to adapt to microenvironmental stresses. Anoikis resistance is a fundamental feature of metastatic cancer cell survival during metastatic cancer progression. However, the mechanisms underlying anoikis resistance in ovarian cancer are still unclear. METHODS: Expressions of miRNA-141 and its downstream targets were evaluated by qPCR, Western blotting, Immunohistochemical (IHC) and in situ hybridization (ISH) assays. The luciferase assays were used to prove KLF12 as the downstream target of miR-141. The cDNA microarray and apoptotic protein arrays were used to identify the targets of miR-141 and KLF12. The competition of KLF12 and Sp1 on survivin promoter was examined by ChIP assay. IHC analysis on ovarian cancer tissue array was used to evaluate the expressions of KLF12 and miR-141 and to show the clinical relevance. The functional studies were performed by in vitro and in vivo tumorigenic assays. RESULTS: Enforced expression of miR-141 promotes, while knockdown of miR-141 expression inhibits, cell proliferation, anchorage-independent capacity, anoikis resistance, tumor growth and peritoneal metastases of ovarian cancer cells. Bioinformatics and functional analysis identified that Kruppel-related zinc finger protein AP-2rep (KLF12) is directly targeted by miR-141. Consistent with this finding, knockdown of KLF12 phenocopied the effects of miR-141 overexpression in ovarian cancer cells. In contrast, restoration of KLF12 in miR-141-expressing cells significantly attenuated anoikis resistance in ovarian cancer cells via interfering with Sp1-mediated survivin transcription, which inhibits the intrinsic apoptotic pathway and is crucial for ovarian cancer cell survival, anoikis resistance and peritoneal metastases. Immunohistochemical (IHC) and in situ hybridization (ISH) assays confirmed that miRNA-141 expression is inversely correlated with KLF12 expression and significantly associated with advanced ovarian cancers accompanied with distal metastases, underscoring the clinical relevance of our findings. CONCLUSIONS: Our data identify a novel signaling axis of miR-141/KLF12/Sp1/survivin in enhancing anoikis resistance and likely serves as a potential therapeutic target for metastatic ovarian cancer.


Assuntos
Anoikis/genética , Proteínas Inibidoras de Apoptose/genética , Fatores de Transcrição Kruppel-Like/genética , MicroRNAs/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fator de Transcrição Sp1/genética , Animais , Sítios de Ligação , Movimento Celular/genética , Proliferação de Células , Sobrevivência Celular/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Metástase Neoplásica , Interferência de RNA , RNA Mensageiro/genética , Survivina , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Acta Biochim Biophys Sin (Shanghai) ; 48(4): 301-17, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26764240

RESUMO

The development and strategic application of effective anticancer therapies have turned out to be one of the most critical approaches of managing human cancers. Nevertheless, drug resistance is the major obstacle for clinical management of these diseases especially ovarian cancer. In the past years, substantial studies have been carried out with the aim of exploring alternative therapeutic approaches to enhance efficacy of current chemotherapeutic regimes and reduce the side effects caused in order to produce significant advantages in overall survival and to improve patients' quality of life. Targeting cancer cell metabolism by the application of AMP-activated protein kinase (AMPK)-activating agents is believed to be one of the most plausible attempts. AMPK activators such as 5-aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside, A23187, metformin, and bitter melon extract not only prevent cancer progression and metastasis but can also be applied as a supplement to enhance the efficacy of cisplatin-based chemotherapy in human cancers such as ovarian cancer. However, because of the undesirable outcomes along with the frequent toxic side effects of most pharmaceutical AMPK activators that have been utilized in clinical trials, attentions of current studies have been aimed at the identification of replaceable reagents from nutraceuticals or traditional medicines. However, the underlying molecular mechanisms of many nutraceuticals in anticancer still remain obscure. Therefore, better understanding of the functional characterization and regulatory mechanism of natural AMPK activators would help pharmaceutical development in opening an area to intervene ovarian cancer and other human cancers.


Assuntos
Adenilato Quinase/metabolismo , Neoplasias Ovarianas/prevenção & controle , Transdução de Sinais , Monofosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Compostos de Bifenilo , Ativadores de Enzimas/farmacologia , Feminino , Humanos , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/metabolismo , Pironas/farmacologia , Tiofenos/farmacologia
17.
Integr Cancer Ther ; 15(3): 376-89, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26487740

RESUMO

UNLABELLED: Objective Acquired chemoresistance is a major obstacle in the clinical management of ovarian cancer. Therefore, searching for alternative therapeutic modalities is urgently needed. Bitter melon (Momordica charantia) is a traditional dietary fruit, but its extract also shows potential medicinal values in human diabetes and cancers. Here, we sought to investigate the extract of bitter melon (BME) in antitumorigenic and cisplatin-induced cytotoxicity in ovarian cancer cells. METHODS: Three varieties of bitter melon were used to prepare the BME. Ovarian cancer cell lines, human immortalized epithelial ovarian cells (HOSEs), and nude mice were used to evaluate the cell cytotoxicity, cisplatin resistance, and tumor inhibitory effect of BME. The molecular mechanism of BME was examined by Western blotting. RESULTS: Cotreatment with BME and cisplatin markedly attenuated tumor growth in vitro and in vivo in a mouse xenograft model, whereas there was no observable toxicity in HOSEs or in nude mice in vivo Interestingly, the antitumorigenic effects of BME varied with different varieties of bitter melon, suggesting that the amount of antitumorigenic substances may vary. Studies of the molecular mechanism demonstrated that BME activates AMP-activated protein kinase (AMPK) in an AMP-independent but CaMKK (Ca(2+)/calmodulin-dependent protein kinase)-dependent manner, exerting anticancer effects through activation of AMPK and suppression of the mTOR/p70S6K and/or the AKT/ERK/FOXM1 (Forkhead Box M1) signaling cascade. CONCLUSION: BME functions as a natural AMPK activator in the inhibition of ovarian cancer cell growth and might be useful as a supplement to improve the efficacy of cisplatin-based chemotherapy in ovarian cancer.


Assuntos
Carcinogênese/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Momordica charantia/química , Neoplasias Ovarianas/tratamento farmacológico , Extratos Vegetais/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Neoplasias Ovarianas/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
18.
PLoS One ; 8(1): e53597, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23301094

RESUMO

Recent evidence has suggested that AMPK activators may be applied as therapeutic drugs in suppressing cancer cell growth. However, the molecular mechanism of their suppressive function in cancer cells is still unclear. Here we show that AMPK activators impair cervical cancer cell growth through the reduction of DVL3, a positive regulator in Wnt/ß-catenin signaling and an oncogenic player in cervical cancer tumorigenesis. By western blot and immunohistochemical analyses, we demonstrated that DVL3 was frequently upregulated and significantly associated with elevated ß-catenin (P = 0.009) and CyclinD1 (P = 0.009) expressions in cervical cancer. Enforced expression of DVL3 elevated ß-catenin and augmented cervical cancer cell growth, verifying that DVL3-mediated Wnt/ß-catenin activation is involved in cervical cancer oncogenesis. On the other aspect, we noted that the cervical cancer cell growth was remarkably suppressed by AMPK activators and such cell growth inhibition was in concomitant with the reduction of DVL3 protein level in dose- and time-dependent manners. Besides, impaired mTOR signaling activity also reduced DVL3 expression. In contrast, co-treatment with Compound C (AMPK inhibitor) could significantly abrogate metformin induced DVL3 reduction. In addition, co-treatment with AM114 or MG132 (proteosomal inhibitors) could partially restore DVL3 expression under the treatment of metformin. Further in vivo ubiquitination assay revealed that metformin could reduce DVL3 by ubiquitin/proteasomal degradation. To our knowledge, this is the first report showing the probable molecular mechanisms of that the AMPK activators suppress cervical cancer cell growth by impairing DVL3 protein synthesis via AMPK/mTOR signaling and/or partially promoting the proteasomal degradation of DVL3.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fosfoproteínas/metabolismo , Neoplasias do Colo do Útero/enzimologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Desgrenhadas , Relação Dose-Resposta a Droga , Ativação Enzimática , Feminino , Células HEK293 , Células HeLa , Humanos , Imuno-Histoquímica/métodos , Plasmídeos/metabolismo , Transdução de Sinais , Fatores de Tempo , Neoplasias do Colo do Útero/metabolismo
19.
PLoS One ; 7(12): e52578, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23285101

RESUMO

Ovarian cancer is a highly lethal disease with poor prognosis and especially in high-grade tumor. Emerging evidence has reported that aberrant upregulation and activation of GRB7, ERK as well as FOXM1 are closely associated with aggresivenesss of human cancers. However, the interplay between these factors in the pathogenesis of human cancers still remains unclear. In this study, we found that GRB7 (P<0.0001), ERK phosphorylation (P<0.0001) and FOXM1 (P = 0.001) were frequently increased and associated with high-grade tumors, as well as a high tendency in association with advanced stage ovarian cancer by immunohistochemical analysis. Intriguingly, the expressions of GRB7 (P<0.0001), ERK phosphorylation (P<0.001) and FOXM1 (P<0.001) showed a significant stepwise increase pattern along Grade 1 to Grade 3 ovarian cancers. Biochemical studies using western blot analysis demonstrated that enforced expression or knockdown of GRB7 showed GRB7 could elevate the levels of ERK phosphorylation and FOXM1, whereas enforced expression of FOXM1 could not alter levels of GRB7 and ERK phosphorylation. But inhibition of ERK signaling by U0126 or PD98059 could reduce the level of FOXM1 in GRB7-overexpressing ovarian cancer cells, suggesting that GRB7, ERK and FOXM1 are regulated orderly. Moreover, inhibition of ERK activity by U0126 or PD98059, or decreased FOXM1 expression by Thiostrepton significantly inhibited cell migration/invasion, tumor growth in vitro and in vivo. Collectively, our findings confer that targeting GRB7/ERK/FOXM1 signaling cascade may be a promising molecular therapeutic choice in combating ovarian cancer.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Fatores de Transcrição Forkhead/antagonistas & inibidores , Proteína Adaptadora GRB7/metabolismo , Terapia de Alvo Molecular , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Transdução de Sinais , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Proteína Forkhead Box M1 , Fatores de Transcrição Forkhead/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Fosforilação , Ensaios Antitumorais Modelo de Xenoenxerto
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