Abstract C84: Inhibition of proteasome deubiquitinating activity as a novel cancer therapy.

Abstract

Abstract Tumor cells display enhanced sensitivity to disruptions in the ubiquitin-proteasome system making this an attractive target for the development of anti-cancer therapies. Ubiquitin-tagged substrates are degraded by the 26S proteasome; a multisubunit complex comprising a proteolytic 20S core particle (20S CP) capped by 19S regulatory particles (19S RP). The 20S CP has evolved as an important target for anti-cancer drug development, resulting in the approval of bortezomib (Velcade®) for the treatment of multiple myeloma. Here, we describe the characterization of the small molecule b-AP15 as a novel class of proteasome inhibitor that functions by abrogating the deubiquitinating (DUB) activity of the 19S RP. b-AP15 inhibits the activity of two 19S RP-associated DUBs, UCHL5 and USP14. Consistent with DUB inhibition, treatment with b-AP15 caused the accumulation of polyubiquitinated proteins in treated cells with higher molecular weight compared to bortezomib treatment and induced a stronger proteotoxic response. Importantly, apoptosis induction by b-AP15 differed from that of bortezomib by being insensitive to disruptions of the p53 tumor suppressor and insensitive to overexpression of the intrinsic apoptotic suppressor Bcl-2. Finally, we show that treatment with b-AP15 inhibited tumor progression in human and mouse tumor in vivo models of breast, lung, colon, head & neck carcinoma and inhibited organ infiltration in an acute myeloid leukemia (AML) model. Our results suggest that inhibiting the DUB activity of the 19S RP may be a novel target for the treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C84.