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2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34361004

RESUMO

This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds.


Assuntos
Acetilcisteína/farmacologia , Carcinogênese/efeitos dos fármacos , Estradiol/farmacologia , Estrona/farmacologia , Quinonas/farmacologia , Resveratrol/farmacologia , Animais , Antioxidantes/farmacologia , Carcinogênese/genética , Adutos de DNA , Estradiol/toxicidade , Estrogênios/farmacologia , Estrogênios/toxicidade , Estrona/toxicidade , Humanos , Quinonas/toxicidade
3.
Int J Mol Sci ; 22(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205571

RESUMO

Studies of recent decades have repeatedly demonstrated the cytotoxic effect of selenium-containing compounds on cancer cells of various origins. Particular attention in these studies is paid to methylseleninic acid, a widespread selenium-containing compound of organic nature, for several reasons: it has a selective cytotoxic effect on cancer cells, it is cytotoxic in small doses, it is able to generate methylselenol, excluding the action of the enzyme ß-lyase. All these qualities make methylseleninic acid an attractive substrate for the production of anticancer drugs on its basis with a well-pronounced selective effect. However, the studies available to date indicate that there is no strictly specific molecular mechanism of its cytotoxic effect in relation to different cancer cell lines and cancer models. This review contains generalized information on the dose- and time-dependent regulation of the toxic effect of methylseleninic acid on the proliferative properties of a number of cancer cell lines. In addition, special attention in this review is paid to the influence of this selenium-containing compound on the regulation of endoplasmic reticulum stress and on the expression of seven selenoproteins, which are localized in the endoplasmic reticulum.


Assuntos
Carcinogênese/efeitos dos fármacos , Citotoxinas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Compostos Organosselênicos/toxicidade , Animais , Humanos , Compostos Organosselênicos/uso terapêutico , Selenoproteínas/metabolismo
4.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199457

RESUMO

Polycyclic aromatic hydrocarbons (PAHs) are chemical compounds comprised of carbon and hydrogen molecules in a cyclic arrangement. PAHs are associated with risks to human health, especially carcinogenesis. One form of exposure to these compounds is through ingestion of contaminated food, which can occur during preparation and processing involving high temperatures (e.g., grilling, smoking, toasting, roasting, and frying) as well as through PAHs present in the soil, air, and water (i.e., environmental pollution). Differently from changes caused by microbiological characteristics and lipid oxidation, consumers cannot sensorially perceive PAH contamination in food products, thereby hindering their ability to reject these foods. Herein, the occurrence and biological effects of PAHs were comprehensively explored, as well as analytical methods to monitor their levels, legislations, and strategies to reduce their generation in food products. This review updates the current knowledge and addresses recent regulation changes concerning the widespread PAHs contamination in several types of food, often surpassing the concentration limits deemed acceptable by current legislations. Therefore, effective measures involving different food processing strategies are needed to prevent and reduce PAHs contamination, thereby decreasing human exposure and detrimental health effects. Furthermore, gaps in literature have been addressed to provide a basis for future studies.


Assuntos
Carcinogênese/efeitos dos fármacos , Poluição Ambiental/efeitos adversos , Alimentos/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Benzopirenos/efeitos adversos , Carcinogênese/genética , Carvão Vegetal/efeitos adversos , Culinária , Adutos de DNA/efeitos adversos , Análise de Alimentos , Manipulação de Alimentos , Humanos
5.
Nat Commun ; 12(1): 4193, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234122

RESUMO

Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.


Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/imunologia , Neoplasias Nasofaríngeas/imunologia , Evasão Tumoral/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Viral da Expressão Gênica/imunologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/metabolismo , Camundongos , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virologia , Nasofaringe/imunologia , Nasofaringe/patologia , Nasofaringe/cirurgia , Nasofaringe/virologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Deleção de Sequência , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Evasão Tumoral/efeitos dos fármacos , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Nat Commun ; 12(1): 4651, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330898

RESUMO

The integrated stress response (ISR) is an essential stress-support pathway increasingly recognized as a determinant of tumorigenesis. Here we demonstrate that ISR is pivotal in lung adenocarcinoma (LUAD) development, the most common histological type of lung cancer and a leading cause of cancer death worldwide. Increased phosphorylation of the translation initiation factor eIF2 (p-eIF2α), the focal point of ISR, is related to invasiveness, increased growth, and poor outcome in 928 LUAD patients. Dissection of ISR mechanisms in KRAS-driven lung tumorigenesis in mice demonstrated that p-eIF2α causes the translational repression of dual specificity phosphatase 6 (DUSP6), resulting in increased phosphorylation of the extracellular signal-regulated kinase (p-ERK). Treatments with ISR inhibitors, including a memory-enhancing drug with limited toxicity, provides a suitable therapeutic option for KRAS-driven lung cancer insofar as they substantially reduce tumor growth and prolong mouse survival. Our data provide a rationale for the implementation of ISR-based regimens in LUAD treatment.


Assuntos
Adenocarcinoma/metabolismo , Fosfatase 6 de Especificidade Dupla/metabolismo , Fator de Iniciação 2 em Eucariotos/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Feminino , Humanos , Indóis/farmacologia , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas p21(ras)/genética , Estresse Fisiológico/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Nat Commun ; 12(1): 4413, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285210

RESUMO

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Feminino , Humanos , Mastectomia , Camundongos , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Life Sci ; 280: 119694, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102192

RESUMO

Cancer is a leading cause of death globally. Cancer cell transformation is the result of intricate crosstalk between intracellular components and proteins. A characteristic feature of cancer cells is the ability to reprogram their metabolic pathways to ensure their infinite proliferative potential. Pyruvate kinase muscle isoform 2 (PKM2) is a glycolytic enzyme that plays crucial roles in cancer, apart from carrying out its metabolic roles. PKM2 is involved in all the major events associated with cancer growth. Modulation of PKM2 activity (dimer inhibition or tetramer activation) has been successful in controlling cancer. However, recent studies provide contrary evidences regarding the oncogenic functions of PKM2. Moreover, several studies have highlighted the cancerous roles of PKM1 isoform in certain contexts. The present review aims at providing the current updates regarding PKM2 targeting in cancer. Further, the review discusses the contradictory results that suggest that both the isoforms of PKM can lead to cancer growth. In conclusion, the review emphasizes revisiting the approaches to target cancer metabolism through PKM to find novel and effective targets for anticancer therapy.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Proteínas de Transporte/agonistas , Proteínas de Transporte/análise , Proteínas de Transporte/antagonistas & inibidores , Descoberta de Drogas , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Proteínas de Membrana/agonistas , Proteínas de Membrana/análise , Proteínas de Membrana/antagonistas & inibidores , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Hormônios Tireóideos/agonistas , Hormônios Tireóideos/análise
9.
Life Sci ; 280: 119750, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34171378

RESUMO

The tumor microenvironment (TME) constitutes multiple cell types including cancerous and non-cancerous cells. The intercellular communication between these cells through TME derived exosomes may either enhance or suppress the tumorigenic processes. The tumor-derived exosomes could convert an anti-tumor environment into a pro-tumor environment by inducing the differentiation of stromal cells into tumor-associated cells. The exosomes from tumor-associated stromal cells reciprocally trigger epithelial-to-mesenchymal transition (EMT) in tumor cells, which impose therapeutic resistance and metastasis. It is well known that these exosomes contain the signals of EMT, but how these signals execute chemoresistance and metastasis in tumors remains elusive. Understanding the significance and molecular signatures of exosomes transmitting EMT signals would aid in developing appropriate methods of inhibiting them. In this review, we focus on molecular signatures of exosomes that shuttle between cancer cells and their stromal populations in TME to explicate their impact on therapeutic resistance and metastasis through EMT. Especially Wnt signaling is found to be involved in multiple ways of exosomal transport and hence we decipher the biomolecules of Wnt signaling trafficked through exosomes and their potential in serving as therapeutic targets.


Assuntos
Transição Epitelial-Mesenquimal , Exossomos/patologia , Neoplasias/patologia , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Comunicação Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Humanos , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos
10.
Toxicol Appl Pharmacol ; 426: 115633, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34166680

RESUMO

Chronic exposure to environmental arsenic promotes lung cancer. Emerging evidence indicates that compromised host immunity, particularly T cell anti-tumor immunity, may play a critical role in cancer development. However, there is a knowledge gap in terms of the effects of arsenic exposure on T cell anti-tumor immunity and how that may contribute to arsenic lung carcinogenicity. Immunosuppression has been known as a risk factor for many types of cancer, including lung cancer. The development of cancer indicates the success of immunosuppression and escape of cancer cells from host anti-tumor immunity in which T cells are the major component. The anti-tumor immunity is mainly executed by CD8 cytotoxic T cells through their anti-tumor effector function, which can be regulated by immune checkpoint pathways. Some inhibitory receptors on the T cell membrane and their ligands form these pathways, among which programmed death-1 (PD-1), a T cell inhibitory receptor, and its ligand, programmed death-ligand 1 (PD-L1), are best characterized. A/J mice are naturally sensitive to pulmonary carcinogens, prone to develop spontaneous lung tumors later in life and have been frequently used as an animal model for lung tumorigenesis research. Chronic arsenic administration through drinking water has been shown to enhance tumor formation in the lungs of A/J mice. In the current study, using this mouse model we want to determine whether PD-1/PD-L1 plays a role in arsenic-enhanced lung tumorigenesis. The results showed that prolonged arsenic exposure up-regulated PD-1/PD-L1, increased regulatory T cells (Tregs), decreased CD8/Treg ratio, inhibited T cell antitumor function in the lungs and enhanced lung tumor formation, while inhibition of PD-1/PD-L1 restored CD8/Treg ratio and T cell anti-tumor effector function, and mitigated arsenic-enhanced lung tumorigenesis. In addition, inhibition of PD-1/PD-L1 could be a potential preventive strategy to mitigate the tumorigenic action of chronic arsenic exposure.


Assuntos
Arsênio/toxicidade , Antígeno B7-H1/imunologia , Carcinogênese/imunologia , Neoplasias Pulmonares/induzido quimicamente , Receptor de Morte Celular Programada 1/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Carcinogênese/efeitos dos fármacos , Feminino , Imunoglobulina G/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Masculino , Camundongos , Linfócitos T Reguladores/imunologia
11.
Molecules ; 26(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063148

RESUMO

This study aimed to evaluate the cancer chemopreventive activity of vanillic acid (VA) in diethylnitrosamine- and 1,2-dimethylhydrazine-induced liver and colon carcinogenesis in rats. VA did not induce the formation of hepatic glutathione S-transferase placental form (GST-P) positive foci and colonic aberrant crypt foci, demonstrating no carcinogenic activity. VA (75 mg kg-1 body weight) could significantly reduce the number and areas of hepatic GST-P positive foci when administered before carcinogen injections, but no such effect was seen when it was administered after carcinogen injection. No protection was seen in the colon when VA was treated before or after carcinogen injection. Immunohistochemical studies demonstrated the decreased expression of proliferating cell nuclear antigen and the induction of apoptosis. Mechanistic studies showed that VA significantly induced the expression of GSTA-5 and Nrf-2 genes, which are associated with the detoxification system. Likewise, the antiproliferative effect was noticed by the reduction of Cyclin D1 expression. The apoptotic activity may be due to the upregulation of Caspase-3 and Bad levels and downregulation of the Bcl-2 level. These data suggest that VA exhibited significant protection against diethylnitrosamine- and 1,2-dimethylhydrazine-induced hepatocarcinogenesis, which might be related to the induction of the detoxifying enzyme, the reduction of proliferation and the induction of apoptosis.


Assuntos
Carcinogênese/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Substâncias Protetoras/uso terapêutico , Ácido Vanílico/uso terapêutico , 1,2-Dimetilidrazina , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Aspartato Aminotransferases/sangue , Carcinogênese/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dietilnitrosamina , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Masculino , Tamanho do Órgão/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos Wistar , Ácido Vanílico/química , Ácido Vanílico/farmacologia
12.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063173

RESUMO

Recent studies have suggested that flavonoids such as quercetin and probiotics such as Bifidobacterium bifidum (Bf) and Lactobacillus gasseri (Lg) could play a relevant role in inhibiting colon cancer cell growth. Our study investigated the role of dietary supplementation with microencapsulated probiotics (Bf and Lg) along with quercetin in the development of mouse colorectal cancer (CRC). Methods: Adenomatous polyposis coli/multiple intestinal neoplasia (ApcMin/+) mice were fed a standard diet or the same diet supplemented with microencapsulated probiotics (Bf and Lg strains, 107 CFU/100 g food) or both probiotics strains plus microencapsulated quercetin (15 mg/100 g food) for 73 days. Changes in body and organ weights, energy metabolism, intestinal microbiota, and colon tissue were determined. The expression of genes related to the Wnt pathway was also analyzed in colon samples. Results: Dietary supplementation with microencapsulated probiotics or microencapsulated probiotics plus quercetin reduced body weight loss and intestinal bleeding in ApcMin/+ mice. An improvement in energy expenditure was observed after 8 weeks but not after 10 weeks of treatment. A supplemented diet with microencapsulated Bf and Lg reduced the number of aberrant crypt foci (ACF) and adenomas by 45% and 60%, respectively, whereas the supplementation with Bf, Lg and quercetin decreased the number of ACF and adenomas by 57% and 80%, respectively. Microencapsulated Bf and Lg in combination with quercetin could exert inhibition of the canonical Wnt/ß-catenin signaling pathway in the colon of ApcMin/+ mice Conclusions: The administration of microencapsulated Bf and Lg, individually or in combination with quercetin, inhibits the CRC development in ApcMin/+ mice.


Assuntos
Polipose Adenomatosa do Colo/metabolismo , Bifidobacterium bifidum/citologia , Carcinogênese/patologia , Células Imobilizadas/citologia , Neoplasias Colorretais/patologia , Lactobacillus gasseri/citologia , Quercetina/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Carcinogênese/efeitos dos fármacos , Colo/patologia , Contagem de Colônia Microbiana , Neoplasias Colorretais/genética , Metabolismo Energético/efeitos dos fármacos , Fezes/microbiologia , Comportamento Alimentar , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Sangue Oculto , Tamanho do Órgão/efeitos dos fármacos , Probióticos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
13.
Int J Mol Sci ; 22(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946266

RESUMO

Despite significant improvements in clinical management, pancreatic cancer (PC) remains one of the deadliest cancer types, as it is prone to late detection with extreme metastatic properties. The recent findings that pancreatic cancer stem cells (PaCSCs) contribute to the tumorigenesis, progression, and chemoresistance have offered significant insight into the cancer malignancy and development of precise therapies. However, the heterogeneity of cancer and signaling pathways that regulate PC have posed limitations in the effective targeting of the PaCSCs. In this regard, the role for K-RAS, TP53, Transforming Growth Factor-ß, hedgehog, Wnt and Notch and other signaling pathways in PC progression is well documented. In this review, we discuss the role of PaCSCs, the underlying molecular and signaling pathways that help promote pancreatic cancer development and metastasis with a specific focus on the regulation of PaCSCs. We also discuss the therapeutic approaches that target different PaCSCs, intricate mechanisms, and therapeutic opportunities to eliminate heterogeneous PaCSCs populations in pancreatic cancer.


Assuntos
Antineoplásicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Descoberta de Drogas , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Hedgehog/metabolismo , Humanos , Terapia de Alvo Molecular , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores Notch/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
14.
Biochem Biophys Res Commun ; 562: 119-126, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34051575

RESUMO

BACKGROUND: Prostate cancer (PCa) refers to malignant tumors derived from prostate epithelial cells, whose morbidity and mortality rates have been increasing every year. Although new drugs for treating prostate cancer continue to emerge, the unclear mechanism underlying drug targets limits this therapy, thereby constraining identification of effective therapeutic targets. Although GDP dissociation inhibitor 2(GDI2) is highly expressed and closely associated with occurrence and development of many tumors, its role in prostate cancer remains unclear. In this study, we investigated the role of GDI2 and elucidated its underlying mechanism of action in prostate cancer. Moreover, we screened chemotherapeutic drugs that affect GDI2 expression with a view of identifying novel targets for diagnosis and treatment of prostate cancer. METHODS: We performed sequence analyses and functional assays to precisely elucidate the GDI2 role in prostate cancer. Moreover, we induced tumorigenesis in nude mice to verify the role of GDI2 in vivo. Finally, we used the CCK8 assay to ascertain the most suitable IC50 across the three drugs and performed quantitative real time polymerase chain reaction (qRT-PCR) and Western Blot to analyze the effects of drugs on expression of GDI2, p75NTR, and p-NFκB. RESULTS: GDI2 was up-regulated in prostate cancer cells and tissues. Knocking down GDI2 suppressed cell proliferation but promoted cell apoptosis. Interestingly, knocking down GDI2 activated the p75NTR signaling pathway, indicating, for the first time, that p75NTR is negatively correlated with GDI2 expression. CONCLUSION: Taken together, these results indicate that GDI2 is a therapeutic target of paclitaxel. Knocking down of GDI2 inhibits cell proliferation and promotes cell apoptosis via the p75NTR signaling pathway in prostate cancer. Notably, paclitaxel inhibits GDI2 expression, implying that GDI2 may be a promising therapeutic target in prostate cancer.


Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Inibidores de Dissociação do Nucleotídeo Guanina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Paclitaxel/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores de Fator de Crescimento Neural/metabolismo , Transdução de Sinais , Apoptose/efeitos dos fármacos , Apoptose/genética , Carcinogênese/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Progressão da Doença , Avaliação Pré-Clínica de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias da Próstata/genética , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
15.
Nat Commun ; 12(1): 3140, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035258

RESUMO

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3ß lysosomal degradation and activation of Wnt/ß-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/ß-catenin therapies.


Assuntos
Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Endossomos/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Lisossomos/metabolismo , Camundongos , Mutação , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Proteômica , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Análise Serial de Tecidos , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rab de Ligação ao GTP/metabolismo
16.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807620

RESUMO

Glycyrrhizin (GL), an important active ingredient of licorice root, which weakens the proinflammatory effects of high-mobility group box 1 (HMGB1) by blocking HMGB1 signaling. In this study, we investigated whether GL could suppress inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer. ICR mice were divided into four groups (n = 5, each)-control group, GL group, colon cancer (CC) group, and GL-treated CC (CC + GL) group, and sacrificed after 20 weeks. Plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured using an enzyme-linked immunosorbent assay. The colonic tissue samples were immunohistochemically stained with DNA damage markers (8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxy-guanosine), inflammatory markers (COX-2 and HMGB1), and stem cell markers (YAP1 and SOX9). The average number of colonic tumors and the levels of IL-6 and TNF-α in the CC + GL group were significantly lower than those in the CC group. The levels of all inflammatory and cancer markers were significantly reduced in the CC + GL group. These results suggest that GL inhibits the inflammatory response by binding HMGB1, thereby inhibiting DNA damage and cancer stem cell proliferation and dedifferentiation. In conclusion, GL significantly attenuates the pathogenesis of AOM/DSS-induced colorectal cancer by inhibiting HMGB1-TLR4-NF-κB signaling.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Ácido Glicirrízico/farmacologia , Inflamação/tratamento farmacológico , Animais , Azoximetano/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Neoplasias Colorretais/metabolismo , Modelos Animais de Doenças , Feminino , Proteína HMGB1/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos ICR , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
17.
Genes (Basel) ; 12(4)2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920182

RESUMO

Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration.


Assuntos
Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Quinases raf/metabolismo , Proteínas ras/antagonistas & inibidores , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Quinases raf/genética
18.
Nat Commun ; 12(1): 2183, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846348

RESUMO

Here we show that FTO as an N6-methyladenosine (m6A) RNA demethylase is degraded by selective autophagy, which is impaired by low-level arsenic exposure to promote tumorigenesis. We found that in arsenic-associated human skin lesions, FTO is upregulated, while m6A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m6A RNA methylation, and induced malignant transformation and tumorigenesis. FTO deletion inhibited arsenic-induced tumorigenesis. Moreover, in mice, epidermis-specific FTO deletion prevented skin tumorigenesis induced by arsenic and UVB irradiation. Targeting FTO genetically or pharmacologically inhibits the tumorigenicity of arsenic-transformed tumor cells. We identified NEDD4L as the m6A-modified gene target of FTO. Finally, arsenic stabilizes FTO protein through inhibiting p62-mediated selective autophagy. FTO upregulation can in turn inhibit autophagy, leading to a positive feedback loop to maintain FTO accumulation. Our study reveals FTO-mediated dysregulation of mRNA m6A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity.


Assuntos
Adenosina/análogos & derivados , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Arsênio/toxicidade , Autofagia , Carcinogênese/genética , Adenosina/metabolismo , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Sequência de Bases , Carcinogênese/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Epiderme/metabolismo , Ontologia Genética , Células HEK293 , Células HaCaT , Humanos , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos , NF-kappa B/metabolismo , Ubiquitina-Proteína Ligases Nedd4/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Estabilidade de RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína Sequestossoma-1/metabolismo , Transcriptoma/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Vacúolos/efeitos dos fármacos , Vacúolos/metabolismo , Vacúolos/ultraestrutura
19.
Theranostics ; 11(12): 5847-5862, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897885

RESUMO

Metastasis and chemoresistance are major causes of poor prognosis in patients with esophageal squamous cell carcinoma (ESCC), manipulated by multiple factors including deubiquitinating enzyme (DUB). DUB PSMD14 is reported to be a promising therapeutic target in various cancers. Here, we explored the antitumor activity of Thiolutin (THL), the PSMD14 inhibitor, as a new therapy strategy in ESCC. Methods: Through 4-NQO-induced murine ESCC model, we investigated the expression of PSMD14 in esophageal tumorigenesis. Ubiquitin-AMC assay was performed to evaluate DUB activity of PSMD14 with THL treatment. The effect of THL on epithelial-to-mesenchymal transition (EMT), invasion, stemness and chemosensitivity was detected by using in vitro and in vivo experiments. Immunoprecipitation and in vivo ubiquitination assay were conducted to examine whether THL could impair the deubiquitination and stability of SNAIL regulated by PSMD14. Results: Compared with normal esophageal epithelium, PSMD14 was upregulated in 4-NQO-induced murine esophageal epithelium dysplasia and ESCC tissues. THL could significantly weaken DUB activity of PSMD14. Furthermore, the results of in vitro and in vivo assays showed that THL efficiently suppressed motility and stemness and increased sensitivity to cisplatin in ESCC. Mechanically, THL impaired the interaction between PSMD14 and SNAIL, then promoted the ubiquitination and degradation of SNAIL to inhibit EMT which plays a crucial role in ESCC metastasis, stemness and chemosensitivity. TCGA database analysis revealed that high concomitant PSMD14/SNAIL expression predicted shorter overall survival in esophageal cancer. Conclusion: Our findings demonstrate for the first time that suppression of PSMD14/SNAIL axis by THL could be a novel and promising therapeutic approach for ESCC clinical therapy.


Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Transativadores/metabolismo , Animais , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Pirrolidinonas/farmacologia , Ubiquitinação/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
20.
Genes (Basel) ; 12(5)2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922029

RESUMO

Silencing of tumor suppressor genes (TSGs) through epigenetic mechanisms, mainly via abnormal promoter DNA methylation, is considered a main mechanism of tumorigenesis. The abnormal DNA methylation profiles are transmitted from the cancer mother cell to the daughter cells through the involvement of a macromolecular complex in which the ubiquitin-like containing plant homeodomain (PHD), and an interesting new gene (RING) finger domains 1 (UHRF1), play the role of conductor. Indeed, UHRF1 interacts with epigenetic writers, such as DNA methyltransferase 1 (DNMT1), histone methyltransferase G9a, erasers like histone deacetylase 1 (HDAC1), and functions as a hub protein. Thus, targeting UHRF1 and/or its partners is a promising strategy for epigenetic cancer therapy. The natural compound thymoquinone (TQ) exhibits anticancer activities by targeting several cellular signaling pathways, including those involving UHRF1. In this review, we highlight TQ as a potential multitarget single epidrug that functions by targeting the UHRF1/DNMT1/HDAC1/G9a complex. We also speculate on the possibility that TQ might specifically target UHRF1, with subsequent regulatory effects on other partners.


Assuntos
Benzoquinonas/farmacologia , Proteínas Estimuladoras de Ligação a CCAAT/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Carcinogênese/efeitos dos fármacos , Carcinogênese/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos
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