Section 3.2.8: PPAR signaling pathways in CSCs (from DOI: 10.1038/s41392-020-0110-5)
From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8; DOI: https://doi.org/10.1038/s41392-020-0110-5
Section 3.2.8: PPAR signaling pathways in CSCs
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that were first cloned from mouse liver by Isseman and Green. PPARs are also members of the ligand-activated transcription factor superfamily of nuclear hormone receptors that are associated with retinoic acid, steroids and thyroid hormone receptors. PPARs act as fat sensors to regulate the transcription of lipid metabolic enzymes. At present, three subtypes, PPARalpha, PPARbeta, and PPARgamma (encoded by the PPARA, PPARD, and PPARG genes, respectively), have been found. PPARalpha is highly expressed in hepatocytes, cardiac myocytes, intestinal cells, and renal proximal convoluted tubule cells. PPARgamma is abundantly expressed in adipose tissue, vascular parietal cells (such as monocytes/macrophages, ECs, and smooth muscle cells), and myocardial cells. PPARbeta is expressed in almost all tissues of the body, and its expression level is higher than that of PPARalpha or PPARgamma. In recent years, studies have found that PPARs are closely related to energy (lipid and sugar) metabolism, cell differentiation, proliferation, apoptosis, and inflammatory reactions. PPARs can exert positive or negative effects to regulate target gene expression by binding to a specific peroxisome located at each gene regulatory site and a proliferative response element. Their natural ligands are unsaturated fatty acids, eicosane acids, oxidized low-density lipoprotein, very low-density lipoprotein, and linoleic acid derivatives.
To date, there have been many reports about the role of PPARs in cancer cells, including prostate cancer, breast cancer, glioblastoma, neuroblastoma, pancreatic cancer, hepatic cancer, leukemia, and bladder cancer and thyroid tumors. However, the function of PPARs in CSCs is not well understood, except for some reports on PPARgamma. As a tumor suppressor, PPARgamma binds and activates a canonical response element in the miR-15a gene in breast CSCs to reduce the CD49high/CD24+ mesenchymal stem cell (MSC) population and inhibit angiogenesis. PPARgamma activation also prevents cell spheroid formation and stem cell-like properties in bladder CSCs and induces adipocyte differentiation and beta-catenin degradation in adipose tissues. Furthermore, expression of PPARgamma restrains YAP transcriptional activity to induce differentiation in osteosarcoma stem cells and melanoma cells. The PPARgamma/NF-kappaB pathway promotes M2 polarization of macrophages to prevent cell death in ovarian CSCs4. PPARgamma activation promotes expression of its target gene PTEN to inhibit PI3K/Akt/mTOR signaling, which stunts self-renewal, tumorigenicity, and metastasis in cervical CSCs, glioblastoma stem cells, and liver CSCs. However, combined expression of Dnmt3a and Dnmt3b inhibits PPARgamma expression by direct methylation of its promoter in squamous carcinomas. PPARs are also closely related to the metabolism of CSCs. PPARalpha and PPARbeta/delta regulate metabolic reprogramming in glioblastoma stem cells, lung CSCs, and mouse mammary gland cancer. The transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PPARGC1A, also known as PGC-1alpha) promotes CSC proliferation and invasion by enhancing oxidative phosphorylation, mitochondrial biogenesis, and the oxygen consumption rate of breast CSCs. In addition, the AMPK signaling pathway (adenosine 5'-monophosphate (AMP)-activated protein kinase) is an AMP-dependent protein kinase that is a key molecule in the regulation of bioenergy metabolism and is the core of the study of diabetes and other metabolic-related diseases. AMPK is expressed in various CSCs related to metabolism. Some studies have shown that AMPK is necessary for prostate CSCs to maintain glucose balance. Metformin, an antidiabetic drug that fights cancer, targets AMPK signaling to inhibit cell proliferation and metabolism in colorectal CSCs and HCC stem cells. Therefore, metformin may be a potential therapeutic regent by regulating the energy metabolism of CSCs. These studies suggest that PPARs play an important role in the growth of CSCs.
