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Volume 23
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10.3390/ijms232214474
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Article

Bcl-2 Family Members Bcl-xL and Bax Cooperatively Contribute to Bortezomib Resistance in Mantle Cell Lymphoma

by
Sudjit Luanpitpong
1,*,
Montira Janan
1,†,
Juthamas Yosudjai
1,†,
Jirarat Poohadsuan
1,
Pithi Chanvorachote
2,3 and
Surapol Issaragrisil
1,4,5
1
Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
2
Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
3
Cell-Based Drug and Health Product Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
4
Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
5
Bangkok Hematology Center, Wattanosoth Hospital, BDMS Center of Excellence for Cancer, Bangkok 10310, Thailand
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(22), 14474; https://doi.org/10.3390/ijms232214474
Submission received: 10 October 2022 / Revised: 11 November 2022 / Accepted: 19 November 2022 / Published: 21 November 2022
(This article belongs to the Special Issue Molecular Mechanisms of Targeted Therapy in Cancer)
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Abstract

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with poor prognosis, due to the inevitable development of drug resistance. Despite being the first-in-class proteasome inhibitor for relapsed/refractory MCL, resistance to bortezomib (BTZ) in MCL patients remains a major hurdle of effective therapy, and relapse following BTZ is frequent. Understanding the mechanisms underlying BTZ resistance is, therefore, important for improving the clinical outcome and developing novel therapeutic strategies. Here, we established de novo BTZ-resistant human MCL-derived cells with the highest resistance index of 300-fold compared to parental cells. We provided compelling evidence that both Bcl-xL and Bax are key mediators in determining BTZ sensitivity in MCL cells. Overexpression of antiapoptotic Bcl-xL and depletion of proapoptotic Bax cooperatively protected MCL cells against BTZ-induced apoptosis, causing acquired BTZ resistance, likely by tilting the balance of Bcl-2 family proteins toward antiapoptotic signaling. Bioinformatics analyses suggested that high BCL2L1 (encoded Bcl-xL) and low BAX were, in part, associated with poor prognosis of MCL patients, e.g., when combined with low OGT, which regulates cellular O-GlcNAcylation. Our findings support recent strategies in small molecule drug discovery co-targeting antiapoptotic Bcl-2 family proteins using BH3 mimetics and Bax using Bax activators to overcome cancer drug resistance.
Keywords: mantle cell lymphoma; bortezomib resistance; Bcl-2 family proteins; Bcl-xL; Bax; O-GlcNAcylation mantle cell lymphoma; bortezomib resistance; Bcl-2 family proteins; Bcl-xL; Bax; O-GlcNAcylation

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MDPI and ACS Style

Luanpitpong, S.; Janan, M.; Yosudjai, J.; Poohadsuan, J.; Chanvorachote, P.; Issaragrisil, S. Bcl-2 Family Members Bcl-xL and Bax Cooperatively Contribute to Bortezomib Resistance in Mantle Cell Lymphoma. Int. J. Mol. Sci. 2022, 23, 14474. https://doi.org/10.3390/ijms232214474

AMA Style

Luanpitpong S, Janan M, Yosudjai J, Poohadsuan J, Chanvorachote P, Issaragrisil S. Bcl-2 Family Members Bcl-xL and Bax Cooperatively Contribute to Bortezomib Resistance in Mantle Cell Lymphoma. International Journal of Molecular Sciences. 2022; 23(22):14474. https://doi.org/10.3390/ijms232214474

Chicago/Turabian Style

Luanpitpong, Sudjit, Montira Janan, Juthamas Yosudjai, Jirarat Poohadsuan, Pithi Chanvorachote, and Surapol Issaragrisil. 2022. "Bcl-2 Family Members Bcl-xL and Bax Cooperatively Contribute to Bortezomib Resistance in Mantle Cell Lymphoma" International Journal of Molecular Sciences 23, no. 22: 14474. https://doi.org/10.3390/ijms232214474

APA Style

Luanpitpong, S., Janan, M., Yosudjai, J., Poohadsuan, J., Chanvorachote, P., & Issaragrisil, S. (2022). Bcl-2 Family Members Bcl-xL and Bax Cooperatively Contribute to Bortezomib Resistance in Mantle Cell Lymphoma. International Journal of Molecular Sciences, 23(22), 14474. https://doi.org/10.3390/ijms232214474

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