Hsp90 Inhibition Affects Cell Metabolism by Disrupting Mitochondrial Protein Insertion

Mycielska, Maria E.; Wachsmuth, Christian J.; Dettmer, Katja; Wagner, Christine; Oefner, Peter J.; Geissler, Edward K.; Lang, Sven A.

doi:10.24966/cbcm-1943/100002

Cited by 2 publications

(3 citation statements)

References 32 publications

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“…For instance, HSP90 inhibitors, including 17-AAG, have been reported to specifically increase the protein levels of both mitochondrial and nuclear-encoded genes by a posttranscriptional regulation (45) and induce mitochondrial swelling, a hallmark of mitochondrial dysfunction (46). HSP90 inhibition has also been reported to induce a change in cell metabolism to glycolysis and poor incorporation of TOM40 into the mitochondrial membrane (47). Moreover, we cannot exclude the possibility that there is some redundancy and compensatory feedback pathways regulating intracellular MRP-1 expression that enable the cell to withstand chemotherapeutic insult under such conditions.…”

Section: Discussionmentioning

confidence: 99%

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

2015

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Overexpression of plasma membrane multidrug resistance-associated protein 1 (MRP-1) in Ewing's sarcoma (ES) predicts poor outcome. MRP-1 is also expressed in mitochondria, and we have examined the submitochondrial localization of MRP-1 and investigated the mechanism of MRP-1 transport and role of this organelle in the response to doxorubicin. The mitochondrial localization of MRP-1 was examined in ES cell lines by differential centrifugation and membrane solubilization by digitonin. Whether MRP-1 is chaperoned by heat shock proteins (HSPs) was investigated by immunoprecipitation, immunofluorescence microscopy, and HSP knockout using small hairpin RNA and inhibitors (apoptozole, 17-AAG, and NVPAUY). The effect of disrupting mitochondrial MRP-1-dependent efflux activity on the cytotoxic effect of doxorubicin was investigated by counting viable cell number. Mitochondrial MRP-1 is glycosylated and localized to the outer mitochondrial membrane, where it is coexpressed with HSP90. MRP-1 binds to both HSP90 and HSP70, although only inhibition of HSP90β decreases expression of MRP-1 in the mitochondria. Disruption of mitochondrial MRP-1-dependent efflux significantly increases the cytotoxic effect of doxorubicin (combination index, <0.9). For the first time, we have demonstrated that mitochondrial MRP-1 is expressed in the outer mitochondrial membrane and is a client protein of HSP90β, where it may play a role in the doxorubicin-induced resistance of ES.-Roundhill, E., Turnbull, D., Burchill, S. Localization of MRP-1 to the outer mitochondrial membrane by the chaperone protein HSP90β.

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Section: Discussionmentioning

confidence: 99%

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

2015

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“…Indeed, the inhibition of HSP90 causes the attenuation of glycolysis and a metabolic shift toward OXPHOS, and an increased production of succinate, an intermediate of the Krebs cycle. This occurs through a reduction of the incorporation of Tom40 and the incorrect assembly of the mitochondrial TOM complex, a consequent reduction of the import of the voltage dependent anion channels (VDACs) in the mitochondrial membrane and a detachment of the first key enzyme of glycolysis, hexokinase II (HKII), bound to VDAC [78]. It is known that HKII, when bound to VDAC, is more active, as the enzyme can easily find the ATP indispensable for its enzymatic activity.…”

Section: Role Of Hsp90 Family Members In Cancer Hallmarksmentioning

confidence: 99%

“…It is known that HKII, when bound to VDAC, is more active, as the enzyme can easily find the ATP indispensable for its enzymatic activity. The inhibition of HSP90 causes the detachment of HKII from VDAC and the consequent inhibition of glycolytic pathway [78].…”

Section: Role Of Hsp90 Family Members In Cancer Hallmarksmentioning

confidence: 99%

HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy

Condelli

Crispo

Pietrafesa

et al. 2019

Cells

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Heat shock protein 90 (HSP90) molecular chaperones are a family of ubiquitous proteins participating in several cellular functions through the regulation of folding and/or assembly of large multiprotein complexes and client proteins. Thus, HSP90s chaperones are, directly or indirectly, master regulators of a variety of cellular processes, such as adaptation to stress, cell proliferation, motility, angiogenesis, and signal transduction. In recent years, it has been proposed that HSP90s play a crucial role in carcinogenesis as regulators of genotype-to-phenotype interplay. Indeed, HSP90 chaperones control metabolic rewiring, a hallmark of cancer cells, and influence the transcription of several of the key-genes responsible for tumorigenesis and cancer progression, through either direct binding to chromatin or through the quality control of transcription factors and epigenetic effectors. In this review, we will revise evidence suggesting how this interplay between epigenetics and metabolism may affect oncogenesis. We will examine the effect of metabolic rewiring on the accumulation of specific metabolites, and the changes in the availability of epigenetic co-factors and how this process can be controlled by HSP90 molecular chaperones. Understanding deeply the relationship between epigenetic and metabolism could disclose novel therapeutic scenarios that may lead to improvements in cancer treatment.

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Hsp90 Inhibition Affects Cell Metabolism by Disrupting Mitochondrial Protein Insertion

Cited by 2 publications

References 32 publications

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

HSP90 Molecular Chaperones, Metabolic Rewiring, and Epigenetics: Impact on Tumor Progression and Perspective for Anticancer Therapy

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