Inhibition of succinate dehydrogenase by the mitochondrial chaperone TRAP1 has anti-oxidant and anti-apoptotic effects on tumor cells.

Giulia Guzzo,Marco Sciacovelli,Paolo Bernardi,Andrea Rasola

doi:10.18632/oncotarget.2472

Abstract

TRAP1 is a mitochondrial chaperone highly expressed in many tumor types; it inhibits respiratory complex II, down-modulating its succinate dehydrogenase (SDH) enzymatic activity. SDH inhibition in turn leads to a pseudohypoxic state caused by succinate-dependent HIF1α stabilization and promotes neoplastic growth. Here we report that TRAP1 inhibition of SDH also shields cells from oxidative insults and from the ensuing lethal opening of the mitochondrial permeability transition pore. This anti-oxidant activity of TRAP1 protects tumor cells from death in conditions of nutrient paucity that mimic those encountered in the neoplasm during the process of malignant accrual, and it is required for in vitro tumorigenic growth. Our findings demonstrate that SDH inhibition by TRAP1 is oncogenic not only by inducing pseudohypoxia, but also by protecting tumor cells from oxidative stress.

Highlights

Cancer cells are exposed to conditions that increase their reactive oxygen species (ROS) levels, such as abnormal activation of signal transduction pathways, rewiring of metabolic machinery and aberrant environmental inputs [1,2,3]
We have recently shown that the mitochondrial chaperone TRAP1, which is highly expressed in a variety of tumor cell types [15], decreases the succinate dehydrogenase (SDH) enzymatic activity of respiratory complex II, inhibiting respiration
When TRAP1 expression was reinstalled in shTRAP1 cells by using a mouse cDNA, both global ROS and mitochondrial superoxide levels returned to basal values (Fig. 1D, 1G)

Summary

Introduction

Cancer cells are exposed to conditions that increase their reactive oxygen species (ROS) levels, such as abnormal activation of signal transduction pathways, rewiring of metabolic machinery and aberrant environmental inputs [1,2,3]. To avoid the detrimental effects of oxidative stress, cells must rapidly implement their anti-oxidant defenses to set a novel homeostatic redox equilibrium in early neoplastic phases, in order to adapt to metabolic and signalling changes that unbalance their redox control systems [1, 4]. It was shown [5] that several oncogenes induce a ROS scavenging program that is required for tumor initiation and to escape cell death caused by unrestrained oxidative insults. A detailed comprehension of the mechanisms of ROS control that occur in tumorigenesis could be instrumental for the development of selective anti-neoplastic compounds [2]

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Conclusion