Honokiol Bis-Dichloroacetate Is a Selective Allosteric Inhibitor of the Mitochondrial Chaperone TRAP1

Sánchez-Martín, Carlos; Menon, Daniela; Moroni, Elisabetta; Ferraro, Mariarosaria; Masgras, Ionica; Elsey, Justin; Arbiser, Jack L.; Colombo, Giorgio; Rasola, Andrea

doi:10.1089/ars.2019.7972

Cited by 32 publications

(42 citation statements)

References 50 publications

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“…HDCA is a novel TRAP1-specific inhibitor with antitumor activity. By binding an allosteric site in TRAP1, HDCA inhibits TRAP1 but not Hsp90 ATPase activity in a concentration-dependent manner to enhance SDH activity, thus decreasing tumor cell proliferation and tumorigenic growth ( 87 ). Rondanin et al envisaged a potential strategy for inducing apoptosis by targeting the TRAP1 ATPase domain, with cationic appendages selected as carriers for drug delivery to the mitochondria.…”

Section: Development Of Trap1 Inhibitorsmentioning

confidence: 99%

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

et al. 2021

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Tumor necrosis factor receptor-associated protein 1 (TRAP1), a member of the heat shock protein 90 (Hsp90) chaperone family, protects cells against oxidative stress and maintains mitochondrial integrity. To date, numerous studies have focused on understanding the relationship between aberrant TRAP1 expression and tumorigenesis. Mitochondrial TRAP1 is a key regulatory factor involved in metabolic reprogramming in tumor cells that favors the metabolic switch of tumor cells toward the Warburg phenotype. In addition, TRAP1 is involved in dual regulation of the mitochondrial apoptotic pathway and exerts an antiapoptotic effect on tumor cells. Furthermore, TRAP1 is involved in many cellular pathways by disrupting the cell cycle, increasing cell motility, and promoting tumor cell invasion and metastasis. Thus, TRAP1 is a very important therapeutic target, and treatment with TRAP1 inhibitors combined with chemotherapeutic agents may become a new therapeutic strategy for cancer. This review discusses the molecular mechanisms by which TRAP1 regulates tumor progression, considers its role in apoptosis, and summarizes recent advances in the development of selective, targeted TRAP1 and Hsp90 inhibitors.

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Section: Development Of Trap1 Inhibitorsmentioning

confidence: 99%

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

et al. 2021

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“…Here we find that TRAP1 is highly expressed at the beginning of fish embryogenesis, when it exerts an important bioenergetic role. As previously reported in tumor models (Guzzo et al, 2014, Kowalik et al, 2016, Masgras et al, 2017a, Sanchez-Martin et al, 2020a, Sanchez-Martin et al, 2020b, Sciacovelli et al, 2013, TRAP1 inhibits SDH activity during early Zebrafish development, crucially contributing to a bioenergetic phenotype characterized by low levels of OXPHOS. Absence of TRAP1 causes a delay in early development; this defect is gradually lost during the passage from embryo to larva stages, when oxygen tension increases and TRAP1 levels progressively decline.…”

Section: Discussionmentioning

confidence: 53%

HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia

Rasola

Laquatra

Sánchez-Martín

et al. 2020

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The mitochondrial paralog of the Hsp90 chaperone family TRAP1 is often induced in tumors, but the mechanisms controlling its expression, as well as its physiological functions remain poorly understood. Here, we find that TRAP1 is highly expressed in the early stages of Zebrafish development, and its ablation delays embryogenesis while increasing mitochondrial respiration of fish larvae. TRAP1 expression is enhanced by hypoxic conditions both in developing embryos and in cancer models of Zebrafish and mammals. The TRAP1 promoter contains evolutionary conserved hypoxic responsive elements, and HIF1α stabilization increases TRAP1 levels. TRAP1 inhibition by selective compounds or by genetic knock-out maintains a high level of respiration in Zebrafish embryos after exposure to hypoxia.Our data identify TRAP1 as a primary regulator of mitochondrial bioenergetics in highly proliferating cells following reductions in oxygen tension and HIF1α stabilization.

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“…7A). TRAP1 is the mitochondrial paralog of the heat shock protein 90 (HSP90) family and is widely recognized as a potential anti-cancer drug target across multiple human malignancies, including leukemia [43][44][45][46][47][48][49] . Given that ATPase activity is required for TRAP1 function 50 , we hypothesized that ETS inhibition in leukemic mitochondria exposed to ΔG ATP may be driven by acute activation of TRAP1.…”

Section: Resultsmentioning

confidence: 99%

Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.

Nelson

McLaughlin

Hagen

et al. 2020

Preprint

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Currently there is great interest in developing cytotoxic pharmacotherapies that disrupt mitochondrial energy transduction in cancer. Given that mitochondria are critical to mammalian energy homeostasis, clinical success of a given therapeutic will undoubtedly hinge upon its cancer cell selectivity. That said, how the mitochondrial network is intrinsically remodeled to drive/enable the cancer phenotype remains a biological black box, largely due to limitations in analytical approaches. Herein, we leveraged an in-house diagnostic biochemical workflow to comprehensively evaluate mitochondrial bioenergetic efficiency and capacity in human leukemia. Using this platform, we provide direct evidence that despite minimal changes in absolute respiratory kinetics, leukemic mitochondria are hallmarked by intrinsic limitations in oxidative phosphorylation (OXPHOS) that constrain the network’s ability to contribute to cellular ATP free energy (i.e, ΔGATP) charge. Together, these findings link accelerated oxidative metabolism in leukemia to intrinsic OXPHOS deficiency and provide proof-of-concept that restoring, rather than disrupting, OXPHOS across the leukemic mitochondrial network may represent an untapped, but highly feasible, therapeutic avenue.

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Honokiol Bis-Dichloroacetate Is a Selective Allosteric Inhibitor of the Mitochondrial Chaperone TRAP1

Cited by 32 publications

References 50 publications

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

The Mitochondrial Chaperone TRAP1 as a Candidate Target of Oncotherapy

HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia

Intrinsic oxidative phosphorylation limitations underlie cellular bioenergetics in leukemia.

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