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Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses.

ABSTRACT: Ovarian cancer is the deadliest of the gynecologic malignancies. Carcinogenic progression is accompanied by upregulation of ubiquitin-dependent protein degradation machinery as a mechanism to compensate with elevated endogenous proteotoxic stress. Recent studies support the notion that deubiquitinating enzymes (DUB) are essential factors in proteolytic degradation and that their aberrant activity is linked to cancer progression and chemoresistance. Thus, DUBs are an attractive therapeutic target for ovarian cancer.The potency and selectivity of RA-9 inhibitor for proteasome-associated DUBs was determined in ovarian cancer cell lines and primary cells. The anticancer activity of RA-9 and its mechanism of action were evaluated in multiple cancer cell lines in vitro and in vivo in immunodeficient mice bearing an intraperitoneal ES-2 xenograft model of human ovarian cancer.Here, we report the characterization of RA-9 as a small-molecule inhibitor of proteasome-associated DUBs. Treatment with RA-9 selectively induces onset of apoptosis in ovarian cancer cell lines and primary cultures derived from donors. Loss of cell viability following RA-9 exposure is associated with an unfolded protein response as mechanism to compensate for unsustainable levels of proteotoxic stress. In vivo treatment with RA-9 retards tumor growth, increases overall survival, and was well tolerated by the host.Our preclinical studies support further evaluation of RA-9 as an ovarian cancer therapeutic.

SUBMITTER: Coughlin K

PROVIDER: S-EPMC4269153 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses.

Coughlin Kathleen K Anchoori Ravi R Iizuka Yoshie Y Meints Joyce J MacNeill Lauren L Vogel Rachel Isaksson RI Orlowski Robert Z RZ Lee Michael K MK Roden Richard B S RB Bazzaro Martina M

Clinical cancer research : an official journal of the American Association for Cancer Research 20140411 12

<h4>Purpose</h4>Ovarian cancer is the deadliest of the gynecologic malignancies. Carcinogenic progression is accompanied by upregulation of ubiquitin-dependent protein degradation machinery as a mechanism to compensate with elevated endogenous proteotoxic stress. Recent studies support the notion that deubiquitinating enzymes (DUB) are essential factors in proteolytic degradation and that their aberrant activity is linked to cancer progression and chemoresistance. Thus, DUBs are an attractive th ...[more]

PMID: 24727327

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Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses.

Publications

Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses.

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