Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells

Im, Chang‐Nim

doi:10.1007/s12192-016-0687-3

Cited by 28 publications

(33 citation statements)

References 67 publications

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“…20 TRAP1 is also involved in the regulation of mPTP opening. 21 To assess whether TRAP1 and mPTP opening play a role in BAY-induced cell death, we used a previously described method to measure mPTP opening. 22 In brief, cells are stained with the fluorescent cation tetramethylrhodamine methyl ester (TMRM), which accumulates in the mitochondrial matrix in a Δ ψ -dependent manner.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

et al. 2017

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Inhibition of complex I (CI) of the mitochondrial respiratory chain by BAY 87-2243 ('BAY') triggers death of BRAF V600E melanoma cell lines and inhibits in vivo tumor growth. Here we studied the mechanism by which this inhibition induces melanoma cell death. BAY treatment depolarized the mitochondrial membrane potential (Δψ), increased cellular ROS levels, stimulated lipid peroxidation and reduced glutathione levels. These effects were paralleled by increased opening of the mitochondrial permeability transition pore (mPTP) and stimulation of autophagosome formation and mitophagy. BAY-induced cell death was not due to glucose shortage and inhibited by the antioxidant α-tocopherol and the mPTP inhibitor cyclosporin A. Tumor necrosis factor receptor-associated protein 1 (TRAP1) overexpression in BAY-treated cells lowered ROS levels and inhibited mPTP opening and cell death, whereas the latter was potentiated by TRAP1 knockdown. Knockdown of autophagy-related 5 (ATG5) inhibited the BAY-stimulated autophagosome formation, cellular ROS increase and cell death. Knockdown of phosphatase and tensin homologinduced putative kinase 1 (PINK1) inhibited the BAY-induced Δψ depolarization, mitophagy stimulation, ROS increase and cell death. Dynamin-related protein 1 (Drp1) knockdown induced mitochondrial filamentation and inhibited BAY-induced cell death. The latter was insensitive to the pancaspase inhibitor z-VAD-FMK, but reduced by necroptosis inhibitors (necrostatin-1, necrostatin-1s)) and knockdown of key necroptosis proteins (receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and mixed lineage kinase domain-like (MLKL)). BAY-induced cell death was also reduced by the ferroptosis inhibitor ferrostatin-1 and overexpression of the ferroptosis-inhibiting protein glutathione peroxidase 4 (GPX4). This overexpression also inhibited the BAYinduced ROS increase and lipid peroxidation. Conversely, GPX4 knockdown potentiated BAY-induced cell death. We propose a chain of events in which: (i) CI inhibition induces mPTP opening and Δψ depolarization, that (ii) stimulate autophagosome formation, mitophagy and an associated ROS increase, leading to (iii) activation of combined necroptotic/ferroptotic cell death.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

et al. 2017

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“…The cytosol of mammalian cells contains rather large amounts of HSP90, HSP70, HSP40, and HSP27. A 75 kDa chaperone, tumor necrosis factor receptor-associated protein 1 (TRAP1) or HSPC5 [41], is a member of the HSP90 subfamily and is localized in mitochondria [42]. HSP60 belongs to the class of 'chaperonins' and is mainly present in mitochondria, where it works together with HSP10 [39,40].…”

Section: Molecular Chaperones: Localization Activities and Implicatmentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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“…In spite of these protective functions exerted by TRAP1, its overexpression in transgenic mice leads to fatty liver and increased inflammation after partial hepatectomy (PH) (56). Indeed, PH is a stress factor that boosts proliferation and profound metabolic changes in hepatocytes, which is somehow reminiscent of neoplastic growth, but expression levels of TRAP1 do not change after PH in wild-type animals (57).…”

Section: The Molecular Chaperone Trap1mentioning

confidence: 99%

The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells

et al. 2017

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Mitochondria can receive, integrate, and transmit a variety of signals to shape many biochemical activities of the cell. In the process of tumor onset and growth, mitochondria contribute to the capability of cells of escaping death insults, handling changes in ROS levels, rewiring metabolism, and reprograming gene expression. Therefore, mitochondria can tune the bioenergetic and anabolic needs of neoplastic cells in a rapid and flexible way, and these adaptations are required for cell survival and proliferation in the fluctuating environment of a rapidly growing tumor mass. The molecular bases of pro-neoplastic mitochondrial adaptations are complex and only partially understood. Recently, the mitochondrial molecular chaperone TRAP1 (tumor necrosis factor receptor associated protein 1) was identified as a key regulator of mitochondrial bioenergetics in tumor cells, with a profound impact on neoplastic growth. In this review, we analyze these findings and discuss the possibility that targeting TRAP1 constitutes a new antitumor approach.

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Past, present, and emerging roles of mitochondrial heat shock protein TRAP1 in the metabolism and regulation of cancer stem cells

Cited by 28 publications

References 67 publications

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells

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