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

Biochemical Pharmacology
Xiaonan ZhangStig Linder

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 α,β-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 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-AP15, 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...Continue Reading

References

Jan 16, 2004·Bioorganic & Medicinal Chemistry·Han-Zhong ZhangSui Xiong Cai
Dec 24, 2004·Anatomy and Embryology·Wu QinyangKjell Hultenby
Jan 31, 2008·Cell Stress & Chaperones·Emily J NoonanLawrence E Hightower
Mar 15, 2008·Cancer Research·Dharmalingam SubramaniamShrikant Anant
Nov 26, 2008·The Journal of Cell Biology·Derek NarendraRichard J Youle
Jan 25, 2011·Journal of Proteome Research·Jürgen CoxMatthias Mann
Nov 5, 2011·ACS Chemical Biology·Sandro SantagataA A Leslie Gunatilaka
Nov 8, 2011·Nature Medicine·Pádraig D'ArcyStig Linder
Sep 6, 2012·Proceedings of the National Academy of Sciences of the United States of America·Drew J AdamsStuart L Schreiber
Nov 28, 2012·Investigational New Drugs·Jenny FelthLinda Rickardson
Jan 16, 2013·Biochemical and Biophysical Research Communications·Malin JarviusRolf Larsson
Jun 19, 2013·The Biochemical Journal·Marianna HalasiAndrei L Gartel
Jul 31, 2013·Nature Chemical Biology·Paola MagnaghiAntonella Isacchi
Apr 15, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kathleen CoughlinMartina Bazzaro
Aug 26, 2014·Journal of Cell Science·Hemmo Meyer, Conrad C Weihl
Apr 10, 2015·Chemical Biology & Drug Design·Xin WangStig Linder
Oct 30, 2015·Current Medicinal Chemistry·A OliveiraM M Pinto
Jul 30, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Pandima Devi KasiSeyed Mohammad Nabavi
Apr 21, 2017·Frontiers in Molecular Neuroscience·Benedetta Mannini, Fabrizio Chiti
Mar 21, 2018·Cancer Immunology, Immunotherapy : CII·Korbinian N KroppDaniela Dörfel

❮ Previous
Next ❯

Citations

Mar 7, 2020·Signal Transduction and Targeted Therapy·Lu DengPing Wang
Jul 10, 2019·Oxidative Medicine and Cellular Longevity·Xiaonan ZhangStig Linder
Dec 18, 2019·Nature Communications·Amir Ata SaeiRoman A Zubarev
Jul 9, 2020·International Journal of Molecular Sciences·Paola PellegriniPádraig D Arcy
Aug 28, 2020·Cancers·Claudio Brancolini, Luca Iuliano
Feb 13, 2021·Acta Tropica·Andressa Barban do PatrocínioVanderlei Rodrigues
Apr 17, 2020·Signal Transduction and Targeted Therapy·Lu DengPing Wang
Nov 5, 2020·Journal of Medicinal Chemistry·Martina Bazzaro, Stig Linder

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.