The deubiquitinase inhibitor b-AP15 induces strong proteotoxic stress and mitochondrial damage.

The deubiquitinase inhibitor b-AP15 induces strong proteotoxic stress and mitochondrial damage. Biochem Pharmacol. 2018 Aug 24;: Authors: Zhang X, Pellegrini P, Saei AA, Hillert EK, Mazurkiewicz M, Olofsson MH, Zubarev RA, D'Arcy P, Linder S Abstract Human cancers are characterized by intrinsic or acquired resistance to apoptosis and evasion of apoptosis has been proposed to contribute to treatment resistance. Bis-benzylidine piperidone compounds, containing ,-unsaturated carbonyl functionalities, have been extensively documented as being effective in killing apoptosis-resistant cells and to display promising antineoplastic activities in a number of tumor models. We here explored the phenotypic response of colon cancer cells to b-AP15, a bis-benzylidine piperidone previously shown to inhibit the proteasome deubiquitinases (DUBs) USP14 and UCHL5. Whereas similar overall mRNA and protein expression profiles were induced by b-AP15 and the clinically available proteasome inhibitor bortezomib, b-AP15 induced stronger increases of chaperone expression. b-AP15 also induced a stronger accumulation of polyubiqutinated proteins in exposed cells. These proteins were found to partially colocalize with organelle structures, including mitochondria. Mitochondrial oxidative phosphorylation decreased in cells exposed to b-AP15, a phenomenon enhanced under conditions of severe proteotoxic stress caused by inhibition of the VCP/p97 ATPase and inhibitio...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research