RESUMO
Von Hippel-Lindau (VHL) is an onco-suppressor involved in oxygen and energy-dependent promotion of protein ubiquitination and proteosomal degradation. Loss of function mutations of VHL (VHL-cells) result in organ specific cancers with the best studied example in renal cell carcinomas. VHL has a well-established role in deactivation of hypoxia-inducible factor (HIF-1) and in regulation of PI3K/AKT/mTOR activity. Cell culture metabolomics analysis was utilized to determined effect of VHL and HIF-1α or HIF-2α on metabolism of renal cell carcinomas (RCC). RCC cells were stably transfected with VHL or shRNA designed to silence HIF-1α or HIF-2α genes. Obtained metabolic data was analysed qualitatively, searching for overall effects on metabolism as well as quantitatively, using methods developed in our group in order to determine specific metabolic changes. Analysis of the effect of VHL and HIF silencing on cellular metabolic footprints and fingerprints provided information about the metabolic pathways affected by VHL through HIF function as well as independently of HIF. Through correlation network analysis as well as statistical analysis of significant metabolic changes we have determined effects of VHL and HIF on energy production, amino acid metabolism, choline metabolism as well as cell regulation and signaling. VHL was shown to influence cellular metabolism through its effect on HIF proteins as well as by affecting activity of other factors.
Assuntos
Carcinoma de Células Renais/metabolismo , Inativação Gênica , Neoplasias Renais/metabolismo , Metaboloma , Metabolômica , Espectroscopia de Prótons por Ressonância Magnética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Análise por Conglomerados , Técnicas de Silenciamento de Genes , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metabolômica/métodos , Mutação , Espectroscopia de Prótons por Ressonância Magnética/métodos , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismoRESUMO
Since 1940 chemotherapy has been one of the major therapies used to kill cancer cells. However, conventional standard cytotoxic agents have a low therapeutic index and often show toxicity in healthy cells. Over the past decade, progress in molecular biology and genomics has identified signaling pathways and mutations driving different types of cancer. Genetic and epigenetic alterations that characterize tumor cells have been used in the development of targeted therapy, a very active area of cancer research. Moreover, identification of synthetic lethal interactions between two altered genes in cancer cells shows much promise to target specifically tumor cells. For a long time, apoptosis was considered the principal mechanism by which cells die from chemotherapeutic agents. Autophagy, necroptosis (a programmed cell death mechanism of necrosis), and lysosomal-mediated cell death significantly improve our understanding of how malignancy can be targeted by anticancer treatments. Autophagy is a highly regulated process by which misfolded proteins and organelles reach lysosomes for their degradation. Alterations in this cellular process have been observed in several pathological conditions, including cancer. The role of autophagy in cancer raised a paradox wherein it can act as a tumor suppressor at early stage of tumor development but can also be used by cancer cells as cytoprotection to promote survival in established tumors. It is interesting that autophagy can be targeted by anticancer agents to provoke cancer cell death. This review focuses on the role of autophagy in cancer cells and its potential to therapeutically kill cancer cells.
