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      Arylquins Target Vimentin to Trigger Par-4 Secretion for Tumor Cell Apoptosis

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          Abstract

          The tumor suppressor protein Par-4, which is secreted by normal cells, selectively induces apoptosis in cancer cells. We identified a 3-arylquinoline derivative, designated Arylquin 1, as a potent Par-4 secretagogue in cell cultures and mice. Mechanistically, Arylquin 1 binds to vimentin, displaces Par-4 from vimentin for secretion and triggers the efficient paracrine apoptosis of diverse cancer cells. Thus, targeting vimentin with Par-4 secretagogues efficiently induces paracrine apoptosis of tumor cells.

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          A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells.

          Tao Zhang, Adel Hamza, Xianhua Cao … (2008)
          Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu33 (Hsp90) and Arg167 (Cdc37). Immunoprecipitation confirmed that celastrol (10 micromol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 micromol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 micromol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells.
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            Impaired wound healing in embryonic and adult mice lacking vimentin.

            B. Eckes, E Colucci-Guyon, H Smola … (2000)
            It is generally assumed that the vimentin intermediate filament network present in most mesenchymally-derived cells is in part responsible for the strength and integrity of these cells, and necessary for any tissue movements that require the generation of significant tractional forces. Surprisingly, we have shown that transgenic KO mice deficient for vimentin are apparently able to undergo embryonic development absolutely normally and go onto develop into adulthood and breed without showing any obvious phenotype. However, fibroblasts derived from these mice are mechanically weak and severely disabled in their capacity to migrate and to contract a 3-D collagen network. To assess whether these functions are necessary for more challenging tissue movements such as those driving in vivo tissue repair processes, we have analysed wound healing ability in wild-type versus vimentin-deficient embryos and adult mice. Wounds in vimentin-deficient adult animals showed delayed migration of fibroblasts into the wound site and subsequently retarded contraction that correlated with a delayed appearance of myofibroblasts at the wound site. Wounds made to vimentin-deficient embryos also failed to heal during the 24 hour culture period it takes for wild-type embryos to fully heal an equivalent wound. By DiI marking the wound mesenchyme and following its fate during the healing process we showed that this impaired healing is almost entirely due to a failure of mesenchymal contraction at the embryonic wound site. These observations reveal an in vivo phenotype for the vimentin-deficient mouse, and challenge the dogma that key morphogenetic events occurring during development require generation of significant tractional forces by mesenchymal cells.
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              The tumor suppressor Par-4 activates an extrinsic pathway for apoptosis.

              Ravshan Burikhanov, Yanming Zhao, Anindya Goswami … (2009)
              Prostate apoptosis response-4 (Par-4) is a proapoptotic protein with intracellular functions in the cytoplasm and nucleus. Unexpectedly, we noted Par-4 protein is spontaneously secreted by normal and cancer cells in culture, and by Par-4 transgenic mice that are resistant to spontaneous tumors. Short exposure to endoplasmic reticulum (ER) stress-inducing agents further increased cellular secretion of Par-4 by a brefeldin A-sensitive pathway. Secretion occurred independently of caspase activation and apoptosis. Interestingly, extracellular Par-4 induced apoptosis by binding to the stress response protein, glucose-regulated protein-78 (GRP78), expressed at the surface of cancer cells. The interaction of extracellular Par-4 and cell surface GRP78 led to apoptosis via ER stress and activation of the FADD/caspase-8/caspase-3 pathway. Moreover, apoptosis inducible by TRAIL, which also exerts cancer cell-specific effects, is dependent on extracellular Par-4 signaling via cell surface GRP78. Thus, Par-4 activates an extrinsic pathway involving cell surface GRP78 receptor for induction of apoptosis.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101231976
                Journal ID (pubmed-jr-id): 32624
                Journal ID (nlm-ta): Nat Chem Biol
                Journal ID (iso-abbrev): Nat. Chem. Biol.
                Title: Nature chemical biology
                ISSN (Print): 1552-4450
                ISSN (Electronic): 1552-4469
                Publication date Nihms-submitted: 5 September 2014
                Publication date (Electronic): 14 September 2014
                Publication date (Print): November 2014
                Publication date PMC-release: 01 May 2015
                Volume: 10
                Issue: 11
                Pages: 924-926
                Affiliations
                [1 ]Department of Radiation Medicine, College of Medicine, University of Kentucky, Lexington, KY 40536
                [2 ]Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536
                [3 ]Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536
                [4 ]Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536
                [5 ]Lucille Parker Markey Cancer Center, University of Kentucky, Lexington, KY 40536
                [6 ]Department of Chemistry, College of Arts and Sciences, University of Kentucky, Lexington, KY 40536
                [7 ]Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536
                [8 ]Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, Lexington, KY 40536
                Author notes
                [* ]Address for correspondence: Vivek M. Rangnekar, Ph.D. University of Kentucky, Lexington, KY. vmrang01@ 123456email.uky.edu
                Article
                Manuscript ID: NIHMS621296
                DOI: 10.1038/nchembio.1631
                PMC ID: 4201913
                PubMed ID: 25218743
                SO-VID: d51b82c6-5384-4c1d-994c-74d7d71710f6
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                Subject: Article

                ScienceOpen disciplines: Biochemistry
                Keywords: 3-arylquinolines,par-4,apoptosis,secretagogues
                Data availability:
                ScienceOpen disciplines: Biochemistry
                Keywords: 3-arylquinolines, par-4, apoptosis, secretagogues

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