The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy.

Shulan Xie,Xuanwei Wang,Shuyuan Gan,Shengmei Zhu,Xiaodong Tang,Xianhui Kang

doi:10.3389/fonc.2020.585047

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.

Highlights

Molecular chaperones, including heat shock proteins (Hsps), are a class of ubiquitous intracellular proteins
This review explores the relationship between aberrant expression of Tumor necrosis factor receptor-associated protein 1 (TRAP1) and tumorigenesis, including the molecular mechanisms by which TRAP1 regulates tumor progression; considers the role of TRAP1 in apoptosis; and evaluates the potential therapeutic value of TRAP1 in cancers
This study proposed that TRAP1 causes tumor cells to invade stromal tissue by inducing epithelialmesenchymal transition (EMT) [20], which is implicated in the metastasis of primary tumors [15]

Summary

INTRODUCTION

Molecular chaperones, including heat shock proteins (Hsps), are a class of ubiquitous intracellular proteins. Wu et al showed that TRAP1 knockout substantially decreased the proliferation and migration of glioblastoma multiforme cells, induced apoptosis and G2/M arrest, and inhibited neurosphere recovery and secondary neurosphere formation through its regulatory effects on metabolic reprogramming [18]. These data indicate that the TRAP1 protein may exert oncogenic effects, promoting the proliferation, invasion, and apoptosis resistance of human malignant tumor cells and affecting the prognosis of patients with cancer. TRAP1 knockdown was found to increase ROS levels, promote mitochondrial c-Src activation, and substantially increase cell motility and invasion [11],

Breast Ovary

GBM cell proliferation and migration

Types of cancer Prostate cancer

Findings

CONCLUDING REMARKS AND FUTURE PERSPECTIVES