The Role of PGC1α in Cancer Metabolism and its Therapeutic Implications

PGC1 alpha is a transcription factor coactivator that influences a majority of cellular metabolic pathways. Abnormal expression of PGC1 alpha is associated with several chronic diseases and, in recent years, it has been shown to be a critical controller of cancer development. PGC1 alpha acts as a stress sensor in cancer cells and can be activated by nutrient deprivation, oxidative damage, and chemotherapy. It influences mitochondria respiration, reactive oxygen species defense system, and fatty acid metabolism by interacting with specific transcription factors. The characteristic traits of PGC1 alpha in maintaining metabolic homeostasis promote cancer cell survival and tumor metastasis in harsh microenvironments. Not only does PGC1 alpha act as a coactivator, but is also itself controlled by oncogenes and transcription factors. PGC1 alpha and these molecules can form signaling axes that include PML/PGC1 alpha/PPAR alpha, MITF/PGC1 alpha, and PGC1 alpha/ERR alpha, which are important in regulating metabolic adaptation in specific cancer types. Some of these PGC1 alpha-associated pathways are inherently activated in cancer cells, and others are induced by stress, which enable cancer cells to acquire resistance against therapy. Notably, certain therapeutic-resistant cancer cells are addicted to PGC1 alpha-dependent metabolic activities. Suppression of PGC1 alpha expression resensitizes these cells to therapeutic treatments, which implicates PGC1 alpha as a promising target in cancer molecular classification and therapy. (C)2016 AACR.