Translational control in the stress adaptive response of cancer cells: a novel role for the heat shock protein TRAP1

Abstract

TNF receptor-associated protein 1 (TRAP1), the main mitochondrial member of the heat shock protein (HSP) 90 family, is induced in most tumor types and is involved in the regulation of proteostasis in the mitochondria of tumor cells through the control of folding and stability of selective proteins, such as Cyclophilin D and Sorcin. Notably, we have recently demonstrated that TRAP1 also interacts with the regulatory protein particle TBP7 in the endoplasmic reticulum (ER), where it is involved in a further extra-mitochondrial quality control of nuclear-encoded mitochondrial proteins through the regulation of their ubiquitination/degradation. Here we show that TRAP1 is involved in the translational control of cancer cells through an attenuation of global protein synthesis, as evidenced by an inverse correlation between TRAP1 expression and ubiquitination/degradation of nascent stress-protective client proteins. This study demonstrates for the first time that TRAP1 is associated with ribosomes and with several translation factors in colon carcinoma cells and, remarkably, is found co-upregulated with some components of the translational apparatus (eIF4A, eIF4E, eEF1A and eEF1G) in human colorectal cancers, with potential new opportunities for therapeutic intervention in humans. Moreover, TRAP1 regulates the rate of protein synthesis through the eIF2α pathway either under basal conditions or under stress, favoring the activation of GCN2 and PERK kinases, with consequent phosphorylation of eIF2α and attenuation of cap-dependent translation. This enhances the synthesis of selective stress-responsive proteins, such as the transcription factor ATF4 and its downstream effectors BiP/Grp78, and the cystine antiporter system xCT, thereby providing protection against ER stress, oxidative damage and nutrient deprivation. Accordingly, TRAP1 silencing sensitizes cells to apoptosis induced by novel antitumoral drugs that inhibit cap-dependent translation, such as ribavirin or 4EGI-1, and reduces the ability of cells to migrate through the pores of transwell filters. These new findings target the TRAP1 network in the development of novel anti-cancer strategies.

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

“…Moreover, preferential activation of eIF2α upregulates ATF4-target genes involved in amino acid synthesis and transport [14], as well as in response to oxidative or ER stress itself, and, among others, xCT, the specific subunit of cystine/glutamate antiporter system [15], whose regulation could contribute to the well characterized role of TRAP1 in oxidative stress protection, and BiP/Grp78. Consistently, BiP/Grp78 mRNA expression is decreased in TRAP1 KD cells under basal conditions [13]. Indeed, as stated above, cells expressing high levels of TRAP1 show reduced sensitivity to ER stress inducers, whereas TRAP1 KD cells respond with a much higher compensatory upregulation of BiP/Grp78 under treatment.…”

“…Using several inducible Myc cell models, as well as genetic and pharmacologic tools, Hart et al [26] have recently shown that Myc induction leads to activation of the PERK/eIF2α/ATF4 axis of the UPR, resulting in increased autophagy and protection against ER stress-dependent apoptosis. Similarly, we have demonstrated in CRC that increased TRAP1 expression correlates with increased expression of Myc, Grp78/BiP, ATF4 and increased phosphorylation of eIF2α [7,13,25].…”

“…Indeed, phosphorylation of eIF2α by PERK has been shown to be necessary for the growth of larger solid tumors [24]. As reported above, the role of TRAP1 in favouring eIF2α phosphorylation in cancer cells is well characterized [13,25]. Using several inducible Myc cell models, as well as genetic and pharmacologic tools, Hart et al [26] have recently shown that Myc induction leads to activation of the PERK/eIF2α/ATF4 axis of the UPR, resulting in increased autophagy and protection against ER stress-dependent apoptosis.…”

“…Of note, TRAP1-containing HCT116 cells exhibit higher activation of the eIF2α kinase PERK and, consequently, higher amounts of phospho-eIF2α either before or after ER stress induced by thapsigargin. By contrast, shTRAP1 cells fail to activate eIF2α in response to stress conditions [13]. The ability of TRAP1 to modulate eIF2α phosphorylation is particularly relevant for its cytoprotective properties, since it has been demonstrated that eIF2α phosphorylation induces the preferential translation of a group of stressresponsive mRNAs, including the transcription factor ATF4: accordingly, higher levels of ATF4 were detected in scrambled cells upon amino acid or glucose deprivation.…”

“…This hypothesis sheds some light on the relevance of the TRAP1-Sorcin interaction and the role of the mitochondrial Sorcin isoform in TRAP1 cytoprotective pathway. Indeed, TRAP1 activity is crucial for the expression/ubiquitination of such Sorcin isoform [13], potentially contributing to Sorcin-induced regulation of Ca 2+ homeostasis in mitochondria and participating in the Ca 2+ -dependent MTP regulation. This observation may be relevant in the perspective of evaluating TRAP1 network as a potential molecular target to revert drug resistance.…”