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The deubiquitinase inhibitor b-AP15 induces strong proteotoxic stress and Check for mitochondrial damage
Karolinska Inst, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
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2018 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 156, p. 291-301Article in journal (Refereed) Published
Abstract [en]

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 alpha,beta-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-APIS induced stronger increases of chaperone expression. b-AP15 also induced a stronger accumulation of polyubiquitinated 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-APIS, a phenomenon enhanced under conditions of severe proteotoxic stress caused by inhibition of the VCP/p97 ATPase and inhibition of protein translocation over the ER. We propose that mitochondrial damage caused by the association of misfolded proteins with mitochondrial membranes may contribute to the atypical cell death mode induced by b-AP15 and related compounds. The robust mode of cell death induction by this class of drugs holds promise for treatment of tumor cells characterized by apoptosis resistance.

Place, publisher, year, edition, pages
PERGAMON-ELSEVIER SCIENCE LTD , 2018. Vol. 156, p. 291-301
Keywords [en]
Proteasome; Deubiquitinase; VCP/p97 ATPase; Bis-benzylidine piperidones; Mitochondria
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-152829DOI: 10.1016/j.bcp.2018.08.039ISI: 000448491500028PubMedID: 30149015OAI: oai:DiVA.org:liu-152829DiVA, id: diva2:1265227
Note

Funding Agencies|Swedish Cancer Society; Radiumhemmets forskningsfonder; Knut and Alice Wallenbergs Foundation; Vetenskapsradet; Barncancerfonden

Available from: 2018-11-22 Created: 2018-11-22 Last updated: 2019-06-28

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