The mitochondrial chaperone TRAP1 drives transformation by inhibiting oxidative phosphorylation.

  • Major finding: The mitochondrial chaperone TRAP1 drives transformation by inhibiting oxidative phosphorylation.

  • Concept: Inhibition of succinate dehydrogenase leads to the stabilization of HIF-1α under normoxic conditions.

  • Impact: Targeting TRAP1 may reverse adaptive metabolic changes in cancer cells and inhibit tumor growth.

To support increased biosynthesis, rapidly proliferating cancer cells undergo a metabolic shift to aerobic glycolysis in a phenomenon known as the Warburg effect, but the mechanisms by which oxidative phosphorylation is suppressed in tumors is incompletely understood. Sciacovelli and colleagues found that the mitochondrial chaperone protein TNF receptor–associated protein 1 (TRAP1) bound and inhibited the enzymatic activity of the electron transport chain component succinate dehydrogenase (SDH) and maintained low levels of oxygen consumption and oxidative phosphorylation in cancer cells. TRAP1 expression is more highly expressed in human cancers than normal tissue, and TRAP1 overexpression was associated with decreased SDH activity in colorectal cancer samples, suggesting that TRAP1-dependent inhibition of oxidative phosphorylation may promote tumor growth. Consistent with this possibility, forced expression of TRAP1 in nontransformed cells induced anchorage-independent growth and colony formation in soft agar whereas knockdown of TRAP1 abrogated the transforming potential of cancer cells in an SDH-dependent manner. Moreover, TRAP1 knockdown completely blocked tumor growth in immunocompromised mice. Inhibition of SDH by TRAP1 led to an accumulation of succinate, which is known to stabilize hypoxia-inducible factor 1α (HIF-1α) by inhibiting prolyl hydroxylase activity. Despite normoxic conditions, HIF-1α was exclusively induced in TRAP1-expressing cells undergoing anchorage-independent growth. Furthermore, HIF-1α was required for TRAP1-induced oncogenic transformation, and HIF-1α was strongly expressed in TRAP-positive tumors in vivo. These findings raise the possibility that by inhibiting SDH, TRAP1 may promote tumor growth by activating HIF-1α before hypoxic areas have formed. Given that HIF-1α itself can suppress oxidative phosphorylation, this may create a feed-forward loop that further alters cellular metabolism and drives tumor growth. Targeting this oncogenic metabolic activity of TRAP1 may therefore be an effective therapeutic strategy.

Sciacovelli M, Guzzo G, Morello V, Frezza C, Zheng L, Nannini N, et al. The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. Cell Metab 2013;17:988–99.