@article{6b35bf0551fd40129accc63da1e99f87,
title = "Targeting the Hsp40/Hsp70 chaperone axis as a novel strategy to treat aastration-resistant prostate cancer",
abstract = "Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy. Significance: These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy.",
author = "Moses, {Michael A.} and Kim, {Yeong Sang} and Rivera-Marquez, {Genesis M.} and Nobu Oshima and Watson, {Matthew J.} and Beebe, {Kristin E.} and Catherine Wells and Sunmin Lee and Zuehlke, {Abbey D.} and Hao Shao and Bingman, {William E.} and Vineet Kumar and Malhotra, {Sanjay V.} and Weigel, {Nancy L.} and Gestwicki, {Jason E.} and Trepel, {Jane B.} and Neckers, {Leonard M.}",
note = "Funding Information: The authors thank the investigators listed in Materials and Methods for kindly providing reagents used in this study. In conducting research using animals, the investigators have adhered to the laws of the United States and regulations oftheDepartmentofAgriculture.Intheconduct ofresearchutilizing recombinant DNA, the investigators have adhered to NIH Guidelines for research involving recombinant DNA molecules. This study was supported by funds from the Intramural Research Program, NCI, Center for Cancer Research (to L.M. Neckers and J.B. Trepel), NIH grant NS059690 (to J.E. Gestwicki), the Cancer Prevention & Research Institute of Texas (RP150648, to N.L. Weigel), and the Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program under Award No. W81XWH-16-1-0562 (to L.M. Neckers and J.E. Gestwicki). Funding Information: The authors thank the investigators listed in Materials and Methods for kindly providing reagents used in this study. In conducting research using animals, the investigators have adhered to the laws of the United States and regulations of the Department of Agriculture. In the conduct of research utilizing recombinant DNA, the investigators have adhered to NIH Guidelines for research involving recombinant DNA molecules. This study was supported by funds from the Intramural Research Program, NCI, Center for Cancer Research (to L.M. Neckers and J.B. Trepel), NIH grant NS059690 (to J.E. Gestwicki), the Cancer Prevention & Research Institute of Texas (RP150648, to N.L. Weigel), and the Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program under Award No. W81XWH-16-1-0562 (to L.M. Neckers and J.E. Gestwicki). Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",
year = "2018",
month = jul,
day = "15",
doi = "10.1158/0008-5472.CAN-17-3728",
language = "English (US)",
volume = "78",
pages = "4022--4035",
journal = "Cancer Research",
issn = "0008-5472",
number = "14",
}