RESUMO
Ovarian cancer has emerged as a multifaceted and genomically complex disease. Genetic/epigenetic mutations, suppression of tumor suppressors, overexpression of oncogenes, rewiring of intracellular signaling cascades and loss of apoptosis are some of the deeply studied mechanisms. In vitro and in vivo studies have highlighted different molecular mechanisms that regulate tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis in ovarian cancer. In this review, we bring to limelight, expansion in understanding systematical characterization of ovarian cancer cells has led to the rapid development of new drugs and treatments to target negative regulators of TRAIL mediated signaling pathway. Wide ranging synthetic and natural agents have been shown to stimulate mRNA and protein expression of death receptors. This review is compartmentalized into programmed cell death protein 4, platelet-derived growth factor signaling and miRNA control of TRAIL mediated signaling to ovarian cancer. Mapatumumab and PRO95780 have been tested for efficacy against ovarian cancer. Use of high-throughput screening assays will aid in dissecting the heterogeneity of this disease and increasing a long-term survival which might be achieved by translating rapidly accumulating information obtained from molecular and cellular studies to clinic researches.
Assuntos
Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Apoptose , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , NF-kappa B/metabolismo , Neoplasias Ovarianas/patologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/genética , Cadeia B de alfa-Cristalina/genética , Cadeia B de alfa-Cristalina/metabolismoRESUMO
Increasing attention is being devoted to the mechanisms by which cells receive signals and then translate these into decisions for growth, death, or migration. Recent findings have presented significant breakthroughs in developing a deeper understanding of the activation or repression of target genes and proteins in response to various stimuli and of how they are assembled during signal transduction in cancer cells. Detailed mechanistic insights have unveiled new maps of linear and integrated signal transduction cascades, but the multifaceted nature of the pathways remains unclear. Although new layers of information are being added regarding mechanisms underlying ovarian cancer and how polymorphisms in VDR gene influence its development, the findings of this research must be sequentially collected and re-interpreted. We divide this multi-component review into different segments: how vitamin D modulates molecular network in ovarian cancer cells, how ovarian cancer is controlled by tumor suppressors and oncogenic miRNAs and finally how vitamin D signaling regulates miRNA expression. Intra/inter-population variability is insufficiently studied and a better understanding of genetics of population will be helpful in getting a step closer to personalized medicine.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Ovarianas/genética , Receptores de Calcitriol/genética , Vitamina D/metabolismo , Apoptose/genética , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Receptores de Calcitriol/metabolismo , Transdução de Sinais/genéticaRESUMO
HPV encoded proteins can elicit ectopic protein-protein interactions that re-wire signaling pathways, in a mode that promotes malignancy. Moreover, accumulating data related to HPV is now providing compelling substantiation of a central role played by HPV in escaping immunosurveillance and impairment of apoptotic response. What emerges is an intricate network of Wnt, TGF, Notch signaling cascades that forms higher-order ligand-receptor complexes routing downstream signaling in HPV infected cells. These HPV infected cells are regulated both extracellularly by ligand receptor axis and intracellularly by HPV encoded proteins and impair TRAIL mediated apoptosis. We divide this review into different sections addressing how linear signaling pathways integrate to facilitate carcinogenesis and compounds that directly or indirectly reverse these aberrant interactions offer new possibilities for therapy in cancer. Although HPV encoded proteins mediated misrepresentation of pathways is difficult to target, improved drug-discovery platforms and new technologies have facilitated the discovery of agents that can target dysregulated pathways in HPV infected cervical cancer cells, thus setting the stage for preclinical models and clinical trials.