2011/05/02

The metabolism of cancer: Warburg effect mediated by ROS and HIF

In Cancer cells, the reprogramming of cellular metabolism requires a glycolitic shift that provides the source of lipids, amino acids and nucleic acids needed for tumor progression and proliferation. Critical roles for posttranslational modifications of proteins have emerged in cancer. Among them, histone deacetylase SIRT3 has been recently identified as a genomically expressed, mitochondria-localized tumor suppressor (Kim et al 2010). The loss of SIRT3 activity suppresses FOXO3a leading to an increase in cellular ROS signaling, which has been linked to malignant transformation. Beyond confirming the tumor suppressor role of SIRT3, researchers at Harvard Medical School in collaboration with a group from CIC bioGUNE, have stepped forward by revealing that this function is mediated by an increase in the stabilization of HIF1 in a ROS dependent-manner. HIF activity is essential for survival and proliferation of tumoral cells in addition to directly affect other functions involved in tumor progression and metastasis. The researches established the mechanism underlying the lack of SIRT3 mediated by ROS dependent inhibition of prolyl hydroxylase (PHD). Suprisingly, the loss of SIRT3 through HIF expression, drives substrate utilization toward a dependence on glucose. Finally, strong evidences have been established between the loss of SIRT3 in human breast cancer and an increased expression of genes related with HIF activity. These findings highlight the connection between metabolic reprogramming and the axis ROS/HIF, opening new therapeutic strategies for drug targeting.