Inhibition of the Lipid Droplet–Peroxisome Proliferator-Activated Receptor α Axis Suppresses Cancer Stem Cell Properties

Abstract

Cancer stem cells (CSCs), having both self-renewal and tumorigenic capacity, utilize an energy metabolism system different from that of non-CSCs. Lipid droplets (LDs) are organelles that store neutral lipids, including triacylglycerol. Previous studies demonstrated that LDs are formed and store lipids as an energy source in some CSCs. LDs play central roles not only in lipid storage, but also as a source of endogenous lipid ligands, which are involved in numerous signaling pathways, including the peroxisome proliferator-activated receptor (PPAR) signaling pathway. However, it remains unclear whether LD-derived signal transduction is involved in the maintenance of the properties of CSCs. We investigated the roles of LDs in cancer stemness using pancreatic and colorectal CSCs and isogenic non-CSCs. PPARα was activated in CSCs in which LDs accumulated, but not in non-CSCs, and pharmacological and genetic inhibition of PPARα suppressed cancer stemness. In addition, inhibition of both re-esterification and lipolysis pathways suppressed cancer stemness. Our study suggested that LD metabolic turnover accompanying PPARα activation is a promising anti-CSC therapeutic target.

Emerging agents that target signaling pathways to eradicate colorectal cancer stem cells

“…PPARs are also involved in the initiation and regulation of CSC functions and in the modulation of the EMT process [ 203 ]. They also regulate lipid droplets, which are organelles that store neutral lipids as an energy source in some CSCs [ 204 ].…”

Dexamethasone Sensitizes Cancer Stem Cells to Gemcitabine and 5-Fluorouracil by Increasing Reactive Oxygen Species Production through NRF2 Reduction

“…The cancer stem-like cell (CSLC) lines used in this study (PANC-1 CSLC, PSN-1 CSLC, WiDr CSLC, and A2780 CSLC) were established from PANC-1, PSN-1, WiDr, and A2780, respectively, using previously published protocols [ 19 , 20 , 21 ]. Briefly, cells were cultured on non-coated dishes in stem cell culture media described below.…”

“…To enrich cancer stem-like cells, the cells were implanted subcutaneously into nude mice before (for PANC-1 CSLC and PSN-1 CSLC) or after (for A2780 CSLC) the sphere formation, and cells dissociated from the tumors were cultured in non-coated dishes in stem cell culture medium. The established CSLC lines have been characterized by the expression of stem cell markers, such as CD133 and Sox2, as well as a sphere-forming ability [ 19 , 20 , 21 ]. The pancreatic cancer cell line PANC-1 was made available by the Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, and PSN-1 was kindly donated by Dr. T. Yoshida at the National Cancer Center Research Institute, who established the cell line [ 22 ].…”

Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy

“…In addition to directly modulating SREBP, recent research has shown that it was feasible to restrain the stemness of CSCs by regulating the upstream pathways of SREBPs. The signaling pathways of peroxisome proliferator-activated receptor (PPARs) were positively associated with adipogenesis and lipid storage, and supported the mediation of stemness of CSCs, including breast, pancreatic, colorectal and hepatic CSCs (Wang et al, 2013;Ma et al, 2019;Kuramoto et al, 2021). In addition to transcription factors, emerging evidence suggests that non-coding RNAs can mediate the stemness of CSCs by regulating lipid metabolism.…”