ER stress protection in cancer cells: the multifaceted role of the heat shock protein TRAP1

Abstract

Abbreviations TRAPis involved in ER stress protection of cancer cellsTRAP1 (Tumour Necrosis Factor Receptor-Associated Protein 1) is a molecular chaperone, member of the HSP90 family, that contributes to the overall survival of cancer cells and is up-regulated in most tumour types (reviewed in 1). A large body of literature demonstrates that TRAP1 is part of a pro-survival signalling pathway aimed at evading the toxic effects of oxidants and anticancer drugs and plays a role in protecting mitochondria against apoptotic stimuli (reviewed in 2). However, whether its roles are uniformly oncogenic or not is now a matter of intense debate. Interestingly, Yoshida and colleagues [3] propose a more subtle reading of TRAP1 roles in the regulation of cellular metabolism and its impact on tumorigenesis. In fact, an inverse correlation between TRAP1 expression and tumor stage in cervical, bladder, and clear cell renal cell carcinoma was demonstrated. These conflicting observations on TRAP1 "behaviour" in different biological contexts is strictly related to a specific molecular complex/integrated network in which TRAP1 represents one of the focal nodes.Abstract: TRAP1 is an HSP90 chaperone, upregulated in human cancers and involved in organelles' homeostasis and tumor cell metabolism. Indeed, TRAP1 is a key regulator of adaptive responses used by highly proliferative tumors to face the metabolic stress induced by increased demand of protein synthesis and hostile environments. Besides well-characterized roles in prevention of mitochondrial permeability transition pore opening and in regulating mitochondrial respiration, TRAP1 is involved in novel regulatory mechanisms: i) the attenuation of global protein synthesis, ii) the co-translational regulation of protein synthesis and ubiquitination of specific client proteins, and iii) the protection from Endoplasmic Reticulum stress. This provides a crucial role to TRAP1 in maintaining cellular homeostasis through protein quality control, by avoiding the accumulation of damaged or misfolded proteins and, likely, facilitating the synthesis of selective cancer-related proteins. Herein, we summarize how these regulatory mechanisms are part of an integrated network, which enables cancer cells to modulate their metabolism and to face, at the same time, oxidative and metabolic stress, oxygen and nutrient deprivation, increased demand of energy production and macromolecule biosynthesis. The possibility to undertake a new strategy to disrupt such networks of integrated control in cancer cells holds great promise for treatment of human malignancies.

TRAP1 protein signature predicts outcome in human metastatic colorectal carcinoma

“…In addition, TRAP1-silenced colon carcinoma cells exhibited lack of clonogenic ability in vitro and tumor formation in mice xenografts [ 15 ], thus supporting the relevance of TRAP1 in early phases of colon carcinogenesis. It is also noteworthy that about 60% of human CRCs with high TRAP1 expression are characterized by the parallel upregulation of a network of proteins involved in several cell functions, critical for colon carcinogenesis [ 5 , 10 , 11 , 13 , 14 , 18 , 27 , 28 ]. Thus, it is intriguing to speculate that TRAP1 upregulation may represent an early mechanism used by colon cancer cells to adapt to unfavorable environmental conditions and, thus, activate a number of pathways responsible for malignant transformation and tumor progression.…”