The deubiquitinase inhibitor b-AP15 induces strong proteotoxic stress and mitochondrial damage
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Xiaonan Zhang1, Paola Pellegrini2, Amir Ata Saei3
1Department of Oncology-Pathology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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. 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.
Insights
Bis-benzylidine piperidone compounds like b-AP15 show promise for treating apoptosis-resistant cancers. These compounds induce protein aggregation and mitochondrial damage, leading to cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Human cancers often exhibit resistance to apoptosis, hindering treatment efficacy.
- Bis-benzylidine piperidone compounds are known for their anti-cancer properties, particularly against apoptosis-resistant cells.
- b-AP15, a specific compound in this class, inhibits proteasome deubiquitinases (DUBs) USP14 and UCHL5.
Purpose of the Study:
- To investigate the cellular response of colon cancer cells to b-AP15.
- To compare the effects of b-AP15 with bortezomib, a clinically used proteasome inhibitor.
- To elucidate the mechanism of cell death induced by b-AP15 in apoptosis-resistant cancer cells.
Main Methods:
- Analysis of mRNA and protein expression profiles.
- Assessment of polyubiquitinated protein accumulation.
- Microscopy to observe protein colocalization with organelles.
- Measurement of mitochondrial oxidative phosphorylation under various stress conditions.
Main Results:
- b-AP15 induced similar overall gene and protein expression changes as bortezomib but with a stronger increase in chaperone expression.
- Accumulation of polyubiquitinated proteins was more pronounced with b-AP15 and partially colocalized with mitochondria.
- Mitochondrial oxidative phosphorylation decreased upon b-AP15 treatment, especially under proteotoxic stress.
Conclusions:
- Misfolded protein association with mitochondrial membranes may cause mitochondrial damage, contributing to the cell death induced by b-AP15.
- b-AP15 and related compounds induce a robust cell death pathway.
- These findings suggest potential therapeutic applications for b-AP15 in treating apoptosis-resistant tumors.
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