PGC1α: Friend or Foe in Cancer?

The PGC1 family (Peroxisome proliferator-activated receptor γ (PPARγ) coactivators) of transcriptional coactivators are considered master regulators of mitochondrial biogenesis and function. The PGC1α isoform is expressed especially in metabolically active tissues, such as the liver, kidneys and brain, and responds to energy-demanding situations. Given the altered and highly adaptable metabolism of tumor cells, it is of interest to investigate PGC1α in cancer. Both high and low levels of PGC1α expression have been reported to be associated with cancer and worse prognosis, and PGC1α has been attributed with oncogenic as well as tumor suppressive features. Early in carcinogenesis PGC1α may be downregulated due to a protective anticancer role, and low levels likely reflect a glycolytic phenotype. We suggest mechanisms of PGC1α downregulation and how these might be connected to the increased cancer risk that obesity is now known to entail. Later in tumor progression PGC1α is often upregulated and is reported to contribute to increased lipid and fatty acid metabolism and/or a tumor cell phenotype with an overall metabolic plasticity that likely supports drug resistance as well as metastasis. We conclude that in cancer PGC1α is neither friend nor foe, but rather the obedient servant reacting to metabolic and environmental cues to benefit the tumor cell.