The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

Abstract

Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the heat shock protein 90 (Hsp90) chaperone family, protects cells against oxidative stress and maintains mitochondrial integrity. To date, numerous studies have focused on understanding the relationship between aberrant TRAP1 expression and tumorigenesis. Mitochondrial TRAP1 is a key regulatory factor involved in metabolic reprogramming in tumor cells that favors the metabolic switch of tumor cells toward the Warburg phenotype. In addition, TRAP1 is involved in dual regulation of the mitochondrial apoptotic pathway and exerts an antiapoptotic effect on tumor cells. Furthermore, TRAP1 is involved in many cellular pathways by disrupting the cell cycle, increasing cell motility, and promoting tumor cell invasion and metastasis. Thus, TRAP1 is a very important therapeutic target, and treatment with TRAP1 inhibitors combined with chemotherapeutic agents may become a new therapeutic strategy for cancer. This review discusses the molecular mechanisms by which TRAP1 regulates tumor progression, considers its role in apoptosis, and summarizes recent advances in the development of selective, targeted TRAP1 and Hsp90 inhibitors.

Identification and Characterization of HSP90 Gene Family Reveals Involvement of HSP90, GRP94 and Not TRAP1 in Heat Stress Response in Chlamys farreri

“…Zhang et al [56] report the upregulation of TRAP1 expression in various human malignancies. Its aberrant expression may also lead to the development of cancer [57][58][59][60]. In our study, the expression of CfTRAP1 was low and stable during developmental processes, in adult tissues, and under heat stress.…”

Luteolin potentiates low‑dose oxaliplatin‑induced inhibitory effects on cell proliferation in gastric cancer by inducing G2/M cell cycle arrest and apoptosis

“…Key signaling protein affected by luteolin and/or oxaliplatin in MFC cells. TRAP1, ERK1/2, and CDC25C are closely related to G 2 /M cell cycle arrest and apoptosis (33,34). Thus, the changes in expression levels of TRAP1, P-ERK1/2/ERK1/2, and CDC25C proteins in MFC cells treated with luteolin and/or oxaliplatin as mentioned before were examined by western blot analysis.…”

Mitochondrial Metabolism in Melanoma

“…TRAP1 has also been observed to play a role in the regulation of BRAF, subsequently activating the MAPK signaling pathway and inducing the associated metabolic effects described in the BRAF section above [125]. A study on colorectal tumors found a positive correlation between TRAP1 and BRAF levels [42].…”

“…Tumor necrosis factor receptor associated protein 1 (TRAP1), an anti-apoptotic mitochondrial protein in the heat shock protein 90 (HSP90) family, is involved in mitochondrial metabolism and known to be altered in cancers. Its regulatory roles in mitochondria include shifting metabolism towards glycolysis, contributing to mitochondrial stability, and combating oxidative stress by lowering ROS [41,[123][124][125]. TRAP1 knockout cells displayed increased oxygen consumption, decreased glycolytic metabolites, increased citric acid cycle metabolites, and increased ROS [126,127].…”