Landscape of the mitochondrial Hsp90 metabolome in tumours

Abstract

Reprogramming of tumor cell metabolism contributes to disease progression and resistance to therapy, but how this process is regulated on the molecular level is unclear. Here we report that Heat Shock Protein 90 (Hsp90)-directed protein folding in mitochondria controls central metabolic networks in tumor cells, including the electron transport chain, citric acid cycle, fatty acid oxidation, amino acid synthesis, and cellular redox status. Specifically, mitochondrial Hsp90, but not cytosolic Hsp90, binds and stabilizes the electron transport chain Complex II subunit succinate dehydrogenase-B, maintaining cellular respiration under low-nutrient conditions, and contributing to hypoxia-inducible factor-1α-mediated tumorigenesis in patients carrying succinate dehydrogenase-B mutations. Thus, Hsp90-directed proteostasis in mitochondria regulates tumor cell metabolism, and may provide a tractable target for cancer therapy.

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer

“…One possibility is that SNPH operates in concert with other regulators of complex II (39), including survivin (26), to preserve subunit assembly and optimal bioenergetics, especially under stress conditions. In fact, it is intriguing that compared with other mitochondrial respiration complexes, complex II appears especially vulnerable to stress stimuli, including defective mitochondrial protein folding (40)(41)(42) and oxidative damage (the present study).…”

Anti-cancer potential of MAPK pathway inhibition in paragangliomas – effect of different statins on mouse pheochromocytoma cells

“…However, several new therapeutic strategies have been recently tested in model organisms [35][36][37][38], including lovastatin [1]. Previously, statins have been reported to decrease proliferation, survival, cell cycle progression, and migration in other cells including aggressive cancer models, amongst others by MAPK pathway inhibition [10,[25][26][27]29,30,[39][40][41].…”

TRAP1 Is Involved in BRAF Regulation and Downstream Attenuation of ERK Phosphorylation and Cell-Cycle Progression: A Novel Target for BRAF-Mutated Colorectal Tumors

“…Initial studies demonstrated its involvement in maintaining mitochondrial integrity and regulating the mitochondrial transition pore (MTP), via direct folding/ stability regulation on cyclophillin D and, likely, other client proteins critical for MTP opening (11,14,15). More recent evidence suggests that TRAP1 is responsible for additional functions critical to tumor progression, such as reprogramming of tumor cell metabolism (16,17) and extramitochondrial quality control regulation of specific mitochondrial client proteins, most of which are key regulators of the mitochondrial apoptotic pathway (15,18,19,20). In this context, previous data from our group suggest that TRAP1 interacts with the regulatory protein particle TBP7 in the endoplasmic reticulum (ER), where it is involved in (i) quality control of nuclear-encoded mitochondrial proteins through cotranslational regulation of their ubiquitination/degradation (18,20,21), (ii) attenuation of global protein synthesis through activation of the GCN2 and PERK kinase pathways, with consequent phosphorylation of eIF2a and attenuation of cap-dependent translation (21), (iii) parallel enhancement of IRES-dependent translation, likely favoring synthesis of selective cancer-related genes (21), and (iv) consequent protection from ER stress with parallel activation of a cytoprotective UPR response (18,20,22).…”

“…Starting from our unpublished observation showing decreased BRAF protein levels in TRAP1-knockdown (KD) cells and considering that (i) HSP90 chaperones are involved in the regulation of BRAF stability (6, 7), (ii) TRAP1 is a HSP90 chaperone and key regulator of several process driving tumor progression (11,16,17,18,22), and (iii) BRAF is an intracellular kinase controlling tumor cell proliferation, migration, and metastasis (3), we studied the relationship between the TRAP1 network and the BRAF signaling pathway. Herein, we report that, in addition to HSP90 folding regulation, BRAF is under additional control by TRAP1 translational/quality control machinery and that this regulation is relevant to BRAF-dependent control on ERK signaling and cell-cycle progression.…”