Abstract
BackgroundResistance to cell death in the presence of stressful stimuli is one of the hallmarks of cancer cells acquired during multistep tumorigenesis, and knowledge of the molecular mechanism of stress adaptation can be exploited to develop cancer-selective therapeutics. Mitochondria and the endoplasmic reticulum (ER) are physically interconnected organelles that can sense and exchange various stress signals. Although there have been many studies on stress propagation from the ER to mitochondria, reverse stress signals originating from mitochondria have not been well reported.MethodsAfter inactivation of the proteins by pharmacologic and genetic methods, the signal pathways were analyzed by fluorescence microscopy, flow cytometry, MTT assay, and western blotting. A mouse xenograft model was used to examine synergistic anticancer activity and the action mechanism of drugs in vivo.ResultsWe show in this study that mitochondrial heat shock protein 90 (Hsp90) suppresses mitochondria-initiated calcium-mediated stress signals propagating into the ER in cancer cells. Mitochondrial Hsp90 inhibition triggers the calcium signal by opening the mitochondrial permeability transition pore and, in turn, the ER ryanodine receptor, via calcium-induced calcium release. Subsequent depletion of ER calcium activates unfolded protein responses in the ER lumen, thereby increasing the expression of a pro-apoptotic transcription factor, CEBP homologous protein (CHOP). Combined treatment with the ER stressor thapsigargin and the mitochondrial Hsp90 inhibitor gamitrinib augmented interorganelle stress signaling by elevating CHOP expression, and showed synergistic cytotoxic activity exclusively in cancer cells in vitro and in vivo.ConclusionsCollectively, mitochondrial Hsp90s confer cell death resistance to cancer cells by suppressing the mitochondria-initiated calcium-mediated interorganelle stress response.
Highlights
Resistance to cell death in the presence of stressful stimuli is one of the hallmarks of cancer cells acquired during multistep tumorigenesis, and knowledge of the molecular mechanism of stress adaptation can be exploited to develop cancer-selective therapeutics
Mitochondrial Heat shock protein 90 (Hsp90) modulate the mitochondrial calcium store To investigate whether mitochondrial Hsp90s modulate mitochondrial calcium stores, we used the mitochondriatargeted Hsp90 inhibitor gamitrinib, a conjugated of triphenylphosphonium and geldanamycin [33,34]
permeability transition pore (PTP) opening and loss of mitochondrial membrane potential (ΔΨm) occurred within 30 minutes (Figure 1C, tetramethylrhodamine methyl ester (TMRM) staining), whereas cytochrome c release, caspase activation, and cell death were not prominent until after 2 hours (Figure 1C, cytochrome c staining; Figure 1D), suggesting that calcium flux concurs with PTP opening, prior to mitochondrial outer membrane permeabilization (MOMP)
Summary
Resistance to cell death in the presence of stressful stimuli is one of the hallmarks of cancer cells acquired during multistep tumorigenesis, and knowledge of the molecular mechanism of stress adaptation can be exploited to develop cancer-selective therapeutics. Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone regulating the stability and functions of client proteins that are often involved in signal transduction during malignant transformation and progression [2,3]. Hsp and its mitochondrial homolog, tumor necrosis factor receptor-associated protein 1 (TRAP1), are abundant in the mitochondria of many cancer cells [7,8,9,10], and their regulation, client proteins, and cellular functions are quite different from the cytoplasmic Hsp pool [4,11]. Cancer cells elevate mitochondrial Hsp expression, which suppresses Cyp-D function to inhibit the deadly increase of membrane permeability in the organelle [7]. PTP opening upon Cyp-D activation increases mitochondrial inner membrane permeability toward small molecules (
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