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The proteasome deubiquitinase inhibitor b-AP15 enhances DR5 activation-induced apoptosis through stabilizing DR5
You-Take Oh1, Liang Deng1, Jiusheng Deng1
1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Abstract:
b-AP15 and its derivatives block proteasome deubiquitinase (DUB) activity and have been developed and tested in the clinic as potential cancer therapeutic agents. b-AP15 induces apoptosis in cancer cells, but the underlying mechanisms are largely undefined. The current study focuses on studying the modulatory effects of b-AP15 on death receptor 5 (DR5) levels and DR5 activation-induced apoptosis as well as on understanding the underlying mechanisms. Treatment with b-AP15 potently increased DR5 levels including cell surface DR5 in different cancer cell lines with limited or no effects on the levels of other related proteins including DR4, c-FLIP, FADD, and caspase-8. b-AP15 substantially slowed the degradation of DR5, suggesting that it stabilizes DR5. Moreover, b-AP15 effectively augmented apoptosis when combined with TRAIL or the DR5 agonistic antibody AMG655; these effects are DR5-dependent because DR5 deficiency abolished the ability of b-AP15 to enhance TRAIL- or AMG655-induced apoptosis. Therefore, it is clear that b-AP15, and possibly its derivatives, can stabilize DR5 and increase functional cell surface DR5 levels, resulting in enhancement of DR5 activation-induced apoptosis. Our findings suggest that b-AP15 and its derivatives may have potential in sensitizing cancer cells to DR5 activation-based cancer therapy.
Insights
The cancer drug b-AP15 increases levels of death receptor 5 (DR5) on cancer cells, enhancing apoptosis. This mechanism suggests b-AP15 may improve DR5-based cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- b-AP15 is a proteasome deubiquitinase (DUB) inhibitor investigated as a cancer therapeutic.
- b-AP15 induces apoptosis in cancer cells, but its precise mechanisms remain unclear.
- Understanding b-AP15's effects on death receptor pathways is crucial for optimizing its therapeutic potential.
Purpose of the Study:
- To investigate the modulatory effects of b-AP15 on death receptor 5 (DR5) levels.
- To elucidate the role of DR5 activation-induced apoptosis in b-AP15's mechanism of action.
- To explore the potential of b-AP15 in combination cancer therapy.
Main Methods:
- Treatment of various cancer cell lines with b-AP15.
- Analysis of DR5 protein levels, including cell surface expression.
- Assessment of apoptosis induction in response to b-AP15, TRAIL, and DR5 agonistic antibodies.
- Evaluation of DR5-dependent effects using DR5-deficient cancer cells.
Main Results:
- b-AP15 significantly increased DR5 levels, including cell surface expression, across multiple cancer cell lines.
- b-AP15 demonstrated a stabilizing effect on DR5, reducing its degradation.
- The combination of b-AP15 with TRAIL or a DR5 agonistic antibody potentiated apoptosis in a DR5-dependent manner.
- DR5 deficiency abrogated the synergistic apoptotic effects of b-AP15 with TRAIL or DR5 agonistic antibodies.
Conclusions:
- b-AP15 stabilizes DR5 and enhances functional cell surface DR5 levels.
- b-AP15 augments DR5 activation-induced apoptosis.
- b-AP15 and its derivatives show promise in sensitizing cancer cells to DR5-targeted therapies.
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