Pro-survival function of the mitochondrial Hsp90 homolog, TRAP1, in cancer cells and insight into cancer therapy
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- Pro-survival function of the mitochondrial Hsp90 homolog, TRAP1, in cancer cells and insight into cancer therapy
- Park, Hye-Kyung
- Kang, Byoung Heon
- Issue Date
- Graduate School of UNIST
- Heat shock protein (Hsp90) is an ATP dependent chaperone that regulates folding of a wide range of client proteins or substrates, which are involved in cellular signaling pathways for tumorigenesis. The most of Hsp90 is localized in cytoplasm but mitochondrial Hsp90 homologue, tumor necrosis factor receptor-associated protein 1 (TRAP1), has been reported. The TRAP1 is highly elevated in many cancer cell types and human cancer patients compared to normal cells. TRAP1 plays important roles in tumorigenesis including the neoplastic metabolic shift to aerobic glycolysis, tumor cell invasion and metastatasis, inhibition of cell death and development of drug resistance.
A class of TRAP1 inhibitors, named gamitrinibs (GA mitochondrial matrix inhibitors), has been developed through combinatorial chemistry. Gamitrinib consist of geldanamycin, a competitive inhibitor of the ATPase pocket of Hsp90 and TRAP1, conjugated with tandem repeats of tetracyclic guanidinium or triphenylphosphonium for mitochondrial targeting. Gamitrinib not only trigger massive cell death in cultured cancer cells in vitro but also strongly suppress tumor growth in various cancer xenograft or genetic mouse model in vivo. The gamitrinib induced cytotoxicity is attributed to the reactivation of cyclophilin D (CypD), an opener of the permeability transition pore (PTP) located in the mitochondrial inner membrane. PTP opening by CypD activation is often suppressed in cancer cells to avoid cell death by interaction with mitochondrial Hsp90s even under stressful cellular environment. Furthermore, gamitrinibs have been shown to induce organelle-specific stress response and dysregulation of bioenergetics in mitochondria of cancer cells.
Resistance to cell death in the presence of stressful stimuli is one of 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. In this study, we showed that mitochondrial heat shock protein 90 (Hsp90) suppresses mitochondria-initiated calcium-mediated stress signals propagating into the ER in cancer cells. Mitochondrial Hsp90 inhibition with gamitrinib 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, thereby increasing the expression of a pro-apoptotic transcription factor, CEBP homologous protein (CHOP). Combined treatment of the ER stressor thapsigargin with the mitochondrial Hsp90 inhibitor gamitrinib augments interorganelle stress signaling by elevating CHOP expression, and showed synergistic cytotoxic activity exclusively in cancer cells in vitro and in vivo. Collectively, the mitochondrial Hsp90s confer apoptosis resistance to cancer cells by suppressing the mitochondria-initiated calcium-mediated interorganelle stress response. Next, the mitochondria stress inducer, gamibrinib has been exploited, for combination cancer therapy with clinical cancer drug doxorubicin (DOX). DOX, an anthracycline antibiotic with the trade name Adrimycin, is one of the most effective anticancer drugs and has been widely used to treat cancer patients in various combination chemotherapeutic regimens. The antitumor activities of DOX and closely related anthracycline analogs are primarily attributed to DNA damage resulting from the inhibition of DNA topoisomearse II. DOX has also been reported to increase oxygen derived free radicals, which contributes not only to its anticancer activities but also induce a major side effect, irreversible cardiomyopathy in the patients. To mitigate the cardiotoxic side effects of DOX, we explored the efficacy of combination treatment of DOX with gamitrinib. The combination treatment with DOX and gamitrinib showed synergistically increased anticancer activities at suboptimal cytotoxic dose in vitro and in vivo, without augmenting the cardiotoxic side effects. The mechanism of the action is involved in stimulation of cellular stress signaling mediating JNK of CHOP pathways and activation of proapoptotic protein Bim. Depending on cellular context of disparate cancer cell types, the combination treatment induced CHOP and Bim expression and phosphorylation of JNK and Bim, which leads to enhance accumulation of Bim and Bad in the mitochondria. These mechanisms were independent of ROS production and synergistically enhanced apoptosis exclusively in cancer cells in vitro and in vivo. In summary, combined treatment of TRAP1 inhibitors can unleash the full potential of the anticancer activity of various anticancer drugs.
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