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      LANDSCAPE OF THE MITOCHONDRIAL Hsp90 METABOLOME IN TUMORS

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          Abstract

          Reprogramming of tumor cell metabolism contributes to disease progression and resistance to therapy, but how this process is regulated on the molecular level is unclear. Here we report that Heat Shock Protein 90 (Hsp90)-directed protein folding in mitochondria controls central metabolic networks in tumor cells, including the electron transport chain, citric acid cycle, fatty acid oxidation, amino acid synthesis, and cellular redox status. Specifically, mitochondrial Hsp90, but not cytosolic Hsp90, binds and stabilizes the electron transport chain Complex II subunit succinate dehydrogenase-B, maintaining cellular respiration under low-nutrient conditions, and contributing to hypoxia-inducible factor-1α-mediated tumorigenesis in patients carrying succinate dehydrogenase-B mutations. Thus, Hsp90-directed proteostasis in mitochondria regulates tumor cell metabolism, and may provide a tractable target for cancer therapy.

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          p53 regulates mitochondrial respiration.

          Satoaki Matoba, Ju-Gyeong Kang, Willmar Patino … (2006)
          The energy that sustains cancer cells is derived preferentially from glycolysis. This metabolic change, the Warburg effect, was one of the first alterations in cancer cells recognized as conferring a survival advantage. Here, we show that p53, one of the most frequently mutated genes in cancers, modulates the balance between the utilization of respiratory and glycolytic pathways. We identify Synthesis of Cytochrome c Oxidase 2 (SCO2) as the downstream mediator of this effect in mice and human cancer cell lines. SCO2 is critical for regulating the cytochrome c oxidase (COX) complex, the major site of oxygen utilization in the eukaryotic cell. Disruption of the SCO2 gene in human cancer cells with wild-type p53 recapitulated the metabolic switch toward glycolysis that is exhibited by p53-deficient cells. That SCO2 couples p53 to mitochondrial respiration provides a possible explanation for the Warburg effect and offers new clues as to how p53 might affect aging and metabolism.
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            Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.

            Mikko Taipale, Irina Krykbaeva, Martina Koeva … (2012)
            HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Targeting mitochondrial glutaminase activity inhibits oncogenic transformation.

              Jian-Bin Wang, Jon W. Erickson, Reina Fuji … (2010)
              Rho GTPases impact a number of activities important for oncogenesis. We describe a small molecule inhibitor that blocks oncogenic transformation induced by various Rho GTPases in fibroblasts, and the growth of human breast cancer and B lymphoma cells, without affecting normal cells. We identify the target of this inhibitor to be the metabolic enzyme glutaminase, which catalyzes the hydrolysis of glutamine to glutamate. We show that transformed fibroblasts and breast cancer cells exhibit elevated glutaminase activity that is dependent on Rho GTPases and NF-κB activity, and is blocked by the small molecule inhibitor. These findings highlight a previously unappreciated connection between Rho GTPase activation and cellular metabolism and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101528555
                Journal ID (pubmed-jr-id): 37539
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature communications
                ISSN (Electronic): 2041-1723
                Publication date Nihms-submitted: 15 July 2013
                Publication date (Print): 10 July 2013
                Publication date PMC-release: 10 January 2014
                Volume: 4
                Page: 2139
                Affiliations
                [1 ]Prostate Cancer Discovery and Development Program, The Wistar Institute, Philadelphia, PA 19104, USA
                [2 ]Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
                [3 ]Molecular and Cellular Oncogenesis Program and Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA, 19104, USA
                [4 ]Department of Pathology, Tufts Medical Center, Boston, MA 02111, USA
                [5 ]Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
                [6 ]Metabolon, Inc. Durham, NC 27713, USA
                [7 ]Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
                Author notes
                Address correspondence: Dario C. Altieri, M.D., The Wistar Institute Cancer Center, 3601 Spruce Street, Philadelphia, PA 19104, Tel. (215) 495-6970; (215) 495-2638; daltieri@ 123456wistar.org
                Article
                Manuscript ID: NIHMS493446
                DOI: 10.1038/ncomms3139
                PMC ID: 3732457
                PubMed ID: 23842546
                SO-VID: e54a17ac-9ce1-47dd-9453-6b4551d3facd
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Heart, Lung, and Blood Institute : NHLBI
                Award ID: R37 HL054131 || HL
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA118005 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA078810 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: P01 CA140043 || CA
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                Subject: Article

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