Abstract
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.
Highlights
The PGC1 family (Peroxisome proliferator-activated receptor γ (PPARγ) coactivators) isoforms α and β are transcriptional coactivators generally described as master regulators of mitochondrial biogenesis and function, including oxidative phosphorylation (OXPHOS), fatty acid/lipid metabolism, and regulation of reactive oxygen species (ROS) levels [1,2]
We will first briefly review the roles of PGC1α in healthy tissue and disease, and findings related to cancer, in particular carcinomas
Metastatic disease can be considered the endpoint of tumor progression, and the highest metastatic potential is believed to reside in the cancer stem cell, or tumor-initiating cell (TIC), subpopulation whose metabolism is briefly discussed below
Summary
The PGC1 family (Peroxisome proliferator-activated receptor γ (PPARγ) coactivators) isoforms α and β are transcriptional coactivators generally described as master regulators of mitochondrial biogenesis (mitobiogenesis) and function, including oxidative phosphorylation (OXPHOS), fatty acid/lipid metabolism, and regulation of reactive oxygen species (ROS) levels [1,2]. PGC1α in particular is crucial for the rapid adaptation of cells to energy-demanding situations. It is expressed especially in metabolically active tissues, such as the liver, cardiac and skeletal muscle and kidneys, as well as adipose tissue and the brain [1,2]. Considering the central role of various mitochondrial functions in cancer, and the wealth of studies on PGC1α in other diseases, it is somewhat surprising that there is so little on PGC1α and cancer. We will first briefly review the roles of PGC1α in healthy tissue and disease, and findings related to cancer, in particular carcinomas. Genes 2018, 9, 48 of studies, discussion of these diverse findings must, in some cases, include associative rather than proven causalities and connections, and we would like to present this review as a map of interesting uncharted areas for future research
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