Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells

Abstract

Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the HSP90 family, controls a variety of physiological functions, including cell proliferation, differentiation, and survival. Most studies have been devoted to understanding the anti-apoptotic roles of TRAP1 in cancer and targeting it for tumor control in clinical settings. Additionally, we have identified a new role for TRAP1 in regulation of liver regeneration after partial hepatectomy in TRAP1 transgenic mice and cellular proliferation in TRAP1-overexpressing cells, via mitochondrial alterations. Moreover, recent works have indicated a role for TRAP1 in the regulation of cancer stem cells (CSCs) as well as a metabolic switch between mitochondrial respiration and aerobic glycolysis called as "Warburg effect." This review discusses the implications of TRAP1 action for both metabolism and the regulation of CSCs.

Keywords: Apoptosis; Cancer stem cells; Fatty liver; TRAP1; Warburg effect.

Fig. 1

Emerging roles of TRAP1 in metabolism and stemness. TRAP1 prevents apoptosis induced by various stressors. TRAP1 downregulation by iron chelation leads to a cellular senescence-like phenotype. In Drosophila, TRAP1 increases survival of paraquat-induced toxicity. In TRAP1-transgenic mice, partial hepatectomy leads to fatty liver. The role of TRAP1 in stemness is not yet clear. Current mitochondria-targeting HSP90 inhibitors suppress both HSP90 and TRAP1, requiring the development of specific TRAP1 inhibitors

Fig. 2

Effects of TRAP1 overexpression on in vitro and in vivo models. a Mitochondrial morphology by transmission electron microscopy illustrating decreased mitochondrial numbers in stable TRAP1-expressing cell lines (upper panel). Decreased PGC-1α mRNA levels in TRAP1 cells (lower panel). b Altered morphology, enhanced proliferation, and ERK phosphorylation in TRAP1 cells. c Fat accumulation in the liver at 72 h after partial hepatectomy (PH). d Pathological analysis of liver tissues at 72 h after PH in wild-type (WT) and TRAP1 transgenic mice; hematoxylin and eosin (H&E) staining. (a, b reprinted by permission from Im and Seo ( 2014 ); c, d from Im et al. ( 2013 )

Fig. 3

TRAP1 as a switch from oxidative metabolism (oxidative phosphorylation, OXPHOS) to glycolysis in metabolic reprogramming of CSCs. TRAP1 levels alter mitochondrial respiration and fatty acid oxidation, together with cellular accumulation of tricarboxylic acid cycle intermediates, ATP, and ROS. At the same time, TRAP1 deficiency affects glucose metabolism as well as invasiveness (Yoshida et al. 2013)