title: Impact of Posttranslational Modifications on the Anticancer Activity of Hsp90 Inhibitors.
abstract: Molecular chaperones are essential for guarding proteins that are indispensable for normal cellular functions. Heat shock protein 90 (Hsp90) is a vital molecular chaperone in eukaryotes that participates in stabilizing and activating approximately 200 target proteins, called "clients," many of which are involved in signal transduction pathways. Cancer cells however utilize Hsp90 to chaperone an array of mutated and overexpressed oncoproteins to protect them from misfolding and degradation. Therefore, Hsp90 is an attractive target in cancer therapy. Hsp90 chaperone function relies on ATP binding and hydrolysis, which in turn guides its carefully orchestrated conformational changes. This chaperone cycle is fine-tuned by another group of proteins called co-chaperones. They are able to accelerate or decelerate the cycle, allowing Hsp90 to chaperone different clients. Posttranslational modifications (PTMs) can also regulate the chaperone cycle at an epigenetic level thereby tailoring Hsp90 function to suit a specific cell type or environmental condition. Recent evidence suggests that inhibition of the enzymes that catalyze the PTM of Hsp90 can act synergistically with Hsp90 inhibitors, providing a novel therapeutic strategy to enhance the efficacy of Hsp90 inhibitors in cancer cells.
authors.affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, New York, USA; Cancer Research Institute, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Woodford
authors.affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, New York, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA; Cancer Research Institute, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Dunn
authors.affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, New York, USA; Cancer Research Institute, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Jonelle B
authors.initials: JB
authors.lastname: Miller
authors.affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, New York, USA; Cancer Research Institute, SUNY Upstate Medical University, Syracuse, New York, USA.
authors.forename: Sami
authors.initials: S
authors.lastname: Jamal
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.affiliation: Department of Urology, SUNY Upstate Medical University, Syracuse, New York, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA; Cancer Research Institute, SUNY Upstate Medical University, Syracuse, New York, USA. Electronic address: mollapom@upstate.edu.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mollapour
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D000255:Adenosine Triphosphate
keywords: Anticancer drugs; Heat shock protein 90; Kinase; Molecular chaperones; Posttranslational regulation