Joseph W Jackson1, Genesis M Rivera-Marquez1, Kristin Beebe1, Andy D Tran2, Jane B Trepel3, Jason E Gestwicki4, Brian S J Blagg5, Shuichi Ohkubo6, Leonard M Neckers1. 1. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 2. Center for Cancer Research, Confocal Microscopy Core Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 3. Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 4. Department of Pharmaceutical Chemistry and the Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA, USA. 5. Department of Chemistry and Biochemistry, The University of Notre Dame, Notre Dame, IN, USA. 6. Tsukuba Research Center, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
Abstract
BACKGROUND: Platelets play a pivotal role in hemostasis, wound healing, and inflammation, and are thus implicated in a variety of diseases, including cancer. Platelet function is associated with release of granule content, cellular shape change, and upregulation of receptors that promote establishment of a thrombus and maintenance of hemostasis. OBJECTIVES: The role of heat shock proteins (Hsps) in modulating platelet function has been studied for a number of years, but comparative roles of individual Hsps have not been thoroughly examined. METHODS: We utilized a panel of specific inhibitors of Hsp40, Hsp70, Hsp90, and Grp94 (the endoplasmic reticulum homolog of Hsp90) to assess their impact on several aspects of platelet function. RESULTS: Inhibition of each of the aforementioned Hsps reduced alpha granule release. In contrast, there was some selectivity in impacts on dense granule release. Thromboxane synthesis was impaired after exposure to inhibitors of Hsp40, Hsp90, and Grp94, but not after inhibition of Hsp70. Both expression of active glycoprotein IIb/IIIa (GPIIb/IIIa) and fibrinogen-induced platelet shape change were diminished by our inhibitors. In contrast, aggregation was selectively abrogated after inhibition of Hsp40 or Hsp90. Lastly, activated platelet-cancer cell interactions were reduced by inhibition of both Hsp70 and Grp94. CONCLUSIONS: These data suggest the importance of Hsp networks in regulating platelet activity.
BACKGROUND: Platelets play a pivotal role in hemostasis, wound healing, and inflammation, and are thus implicated in a variety of diseases, including cancer. Platelet function is associated with release of granule content, cellular shape change, and upregulation of receptors that promote establishment of a thrombus and maintenance of hemostasis. OBJECTIVES: The role of heat shock proteins (Hsps) in modulating platelet function has been studied for a number of years, but comparative roles of individual Hsps have not been thoroughly examined. METHODS: We utilized a panel of specific inhibitors of Hsp40, Hsp70, Hsp90, and Grp94 (the endoplasmic reticulum homolog of Hsp90) to assess their impact on several aspects of platelet function. RESULTS: Inhibition of each of the aforementioned Hsps reduced alpha granule release. In contrast, there was some selectivity in impacts on dense granule release. Thromboxane synthesis was impaired after exposure to inhibitors of Hsp40, Hsp90, and Grp94, but not after inhibition of Hsp70. Both expression of active glycoprotein IIb/IIIa (GPIIb/IIIa) and fibrinogen-induced platelet shape change were diminished by our inhibitors. In contrast, aggregation was selectively abrogated after inhibition of Hsp40 or Hsp90. Lastly, activated platelet-cancer cell interactions were reduced by inhibition of both Hsp70 and Grp94. CONCLUSIONS: These data suggest the importance of Hsp networks in regulating platelet activity.
Authors: Nataly P Podolnikova; Valentin P Yakubenko; George L Volkov; Edward F Plow; Tatiana P Ugarova Journal: J Biol Chem Date: 2003-06-10 Impact factor: 5.157
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Authors: Yaw Chong Goh; Celestial T Yap; Bao Hua Huang; Andrew D Cronshaw; Bernard P Leung; Paul B S Lai; Simon P Hart; Ian Dransfield; James A Ross Journal: Cell Mol Life Sci Date: 2010-10-16 Impact factor: 9.261