The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells

Abstract

Mitochondria can receive, integrate, and transmit a variety of signals to shape many biochemical activities of the cell. In the process of tumor onset and growth, mitochondria contribute to the capability of cells of escaping death insults, handling changes in ROS levels, rewiring metabolism, and reprograming gene expression. Therefore, mitochondria can tune the bioenergetic and anabolic needs of neoplastic cells in a rapid and flexible way, and these adaptations are required for cell survival and proliferation in the fluctuating environment of a rapidly growing tumor mass. The molecular bases of pro-neoplastic mitochondrial adaptations are complex and only partially understood. Recently, the mitochondrial molecular chaperone TRAP1 (tumor necrosis factor receptor associated protein 1) was identified as a key regulator of mitochondrial bioenergetics in tumor cells, with a profound impact on neoplastic growth. In this review, we analyze these findings and discuss the possibility that targeting TRAP1 constitutes a new antitumor approach.

Downregulation of TRAP1 aggravates injury of H9c2 cardiomyocytes in a hyperglycemic state

“…TRAP1 can protect cells and reduce apoptosis by decreasing the production of reactive oxygen species (ROS) and reducing oxidative stress (6). TRAP1 protects cancer cells from hypoxia-induced mitochondrial dysfunction and cell apoptosis during tumor progression, and is a key regulator of mitochondrial bioenergy that assists tumor cells in avoiding death and damage (7). Therefore, TRAP1 is a potential therapeutic target for designing novel anticancer agents (8).…”

Interaction of germline variants in a family with a history of early‐onset clear cell renal cell carcinoma

“…TRAP1 is a key regulator of mitochondrial bioenergetics in tumor cells. TRAP1 can decrease SDH enzymatic activity, thus resulting in high concentration of succinate, and contributing to tumor cell survival in the stress conditions of neoplastic growth (Masgras, et al, ). Our structural characterization of the TRAP1 variant Thr535Ser suggests that it potentially affects the chaperone activity of TRAP1, involved in quality control of matrix proteins.…”

Repurposing drugs as pro‐oxidant redox modifiers to eliminate cancer stem cells and improve the treatment of advanced stage cancers

“…Tumor necrosis factor receptor‐associated protein 1 (TRAP1 or Hsp75), a mitochondrial chaperone of the heat shock protein 90 (Hsp90) family, is another key regulator of mitochondrial respiration . As a mitochondrial localized disulfide exchanger, TRAP1 binds to and regulates CypD (reviewed in Masgras et al). However, TRAP1 also limits ROS generation from the respiratory chain SDH/complex II, thereby increasing the Ca 2+ threshold required for mPTP opening in cancer cells, protecting them from death stimuli .…”

“…Following increased ROS production promoted by loss of antioxidant defenses in the mitochondrial matrix (eg, TrxR system inhibited by auranofin), mCa 2+ influx/overload of ROS, HK release from the VDAC and opening of the mPTP occurs. Aura, auranofin; CK, creatine kinase in the intermembrane space; CsA, cyclosporine A; CypD, cyclophilin D; HK, hexokinase; IMM, inner mitochondrial membrane; MCU, mitochondrial calcium uniporter; mPTP, mitochondrial permeability transition pore; OMM, outer mitochondrial membrane; RuR, ruthenium red; TrxR, thioredoxin reductase; VDAC, voltage dependent anion channel [Color figure can be viewed at wileyonlinelibrary.com] localized disulfide exchanger, TRAP1 binds to and regulates CypD (reviewed in Masgras et al 130 ). However, TRAP1 also limits ROS generation from the respiratory chain SDH/complex II, thereby increasing the Ca 2+ threshold required for mPTP opening in cancer cells, protecting them from death stimuli.…”