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

Kenta Kuramoto,Keita Togashi,Masahiro Yamamoto,Shuhei Suzuki,Chifumi Kitanaka,Masashi Okada,Tomomi Sanomachi

doi:10.3390/genes12010099

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.

Highlights

Cancer stem cells (CSCs) comprise a small population of cells with self-renewal and tumorigenic capacity, functioning in the tumorigenesis, recurrence, and heterogeneity of tumors
CSCs, we investigated whether the Lipid droplets (LDs)–Peroxisome Proliferator-Activated Receptor α (PPARα) axis is involved in the maintenance of
Among CSCs, which play an important role in tumorigenicity, LD accumulation in those of colorectal cancer, ovarian cancer, and glioblastoma was reported to be higher than in non-CSCs [18,19,20]

Summary

Introduction

Cancer stem cells (CSCs) comprise a small population of cells with self-renewal and tumorigenic capacity, functioning in the tumorigenesis, recurrence, and heterogeneity of tumors. CSCs utilize an energy metabolism system different from that used by nonCSCs, which compose most of the tumor. Non-CSCs preferentially employ glycolysis rather than mitochondrial oxidative phosphorylation (OXPHOS) to produce energy even in a normoxic state. Energy is produced by both glycolysis and mitochondrial respiration in many CSCs [1,2,3,4,5]. Based on these reports, the OXPHOS of CSCs has attracted attention as a therapeutic target [3,5,6,7,8,9].

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Conclusion