Co-operation of MCL-1 and BCL-X(L) anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity
- Author(s)
- Galas-Filipowicz, D; Chavda, SJ; Gong, JN; Huang, DCS; Khwaja, A; Yong, K;
- Journal Title
- Frontiers in Oncology
- Abstract
- INTRODUCTION: BCL-2 family proteins are important for tumour cell survival and drug resistance in multiple myeloma (MM). Although proteasome inhibitors are effective anti-myeloma drugs, some patients are resistant and almost all eventually relapse. We examined the function of BCL-2 family proteins in stromal-mediated resistance to carfilzomib-induced cytotoxicity in MM cells. METHODS: Co-cultures employing HS5 stromal cells were used to model the interaction with stroma. MM cells were exposed to CFZ in a 1-hour pulse method. The expression of BCL-2 family proteins was assessed by flow cytometry and WB. Pro-survival proteins: MCL-1, BCL-2 and BCL-X(L) were inhibited using S63845, ABT-199 and A-1331852 respectively. Changes in BIM binding partners were examined by immunoprecipitation and WB. RESULTS: CFZ induced dose-dependent cell death of MM cells, primarily mediated by apoptosis. Culture of MM cells on HS-5 stromal cells resulted in reduced cytotoxicity to CFZ in a cell contact-dependent manner, upregulated expression of MCL-1 and increased dependency on BCL-X(L). Inhibiting BCL-X(L) or MCL-1 with BH-3 mimetics abrogated stromal-mediated protection only at high doses, which may not be achievable in vivo. However, combining BH-3 mimetics at sub-therapeutic doses, which alone were without effect, significantly enhanced CFZ-mediated cytotoxicity even in the presence of stroma. Furthermore, MCL-1 inhibition led to enhanced binding between BCL-X(L) and BIM, while blocking BCL-X(L) increased MCL-1/BIM complex formation, indicating the cooperative role of these proteins. CONCLUSION: Stromal interactions alter the dependence on BCL-2 family members, providing a rationale for dual inhibition to abrogate the protective effect of stroma and restore sensitivity to CFZ.
- Publisher
- Frontiers
- Keywords
- Bcl-xl; BH3 mimetic; Mcl-1; anti-apoptotic proteins; carfilzomib; drug resistance; stromal cells
- Research Division(s)
- Blood Cells and Blood Cancer
- PubMed ID
- 38651147
- Publisher's Version
- https://doi.org/10.3389/fonc.2024.1394393
- Open Access at Publisher's Site
https://doi.org/ 10.3389/fonc.2024.1394393- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-09-23 11:15:46
Last Modified: 2025-09-23 11:16:09