The Role of PGC1a in Cancer Metabolism and its Therapeutic Implications

摘要

PGC1a is a transcription factor coactivator that influences a majority of cellular metabolic pathways. Abnormal expression of PGC1a is associated with several chronic diseases and, in recent years, it has been shown to be a critical controller of cancer development. PGC1a 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 PGC1a in maintaining metabolic homeostasis promote cancer cell survival and tumor metastasis in harsh microenviron-ments. Not only does PGC1a act as a coactivator, but is also itself controlled by oncogenes and transcription factors. PGC1a and these molecules can form signaling axes that include PML/ PGC1a/PPARa, MITF/PGC1a, and PGC1a/ERRa, which are important in regulating metabolic adaptation in specific cancer types. Some of these PGC1a-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 PGC1a-dependent metabolic activities. Suppression of PGC1a expression resensitizes these cells to therapeutic treatments, which implicates PGC1a as a promising target in cancer molecular classification and therapy.