Selective BH3 mimetics synergize with BET inhibition to induce mitochondrial apoptosis in rhabdomyosarcoma cells
| العنوان: | Selective BH3 mimetics synergize with BET inhibition to induce mitochondrial apoptosis in rhabdomyosarcoma cells |
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| المؤلفون: | Ufuk Erdogdu, Nadezda Dolgikh, Stephanie Laszig, Vinzenz Särchen, Michael T. Meister, Marek Wanior, Stefan Knapp, Cathinka Boedicker |
| المصدر: | Neoplasia: An International Journal for Oncology Research, Vol 24, Iss 2, Pp 109-119 (2022) Neoplasia (New York, N.Y.) Neoplasia |
| بيانات النشر: | Elsevier BV, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | BH3 mimetics, PBMC, peripheral blood mononuclear cell, Cancer Research, chemical and pharmacologic phenomena, Antineoplastic Agents, Nerve Tissue Proteins, Receptors, Cell Surface, Apoptosis, PI, propidium iodide, BRD4, bromodomain-containing protein 4, MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Biomimetics, hemic and lymphatic diseases, Cell Line, Tumor, Proto-Oncogene Proteins, Rhabdomyosarcoma, BRD, bromodomain, Humans, BET proteins, RC254-282, Original Research, EV, empty vector, zVAD.fmk, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, ATCC, American Type Culture Collection, mBCL-2, murine BCL-2, CI, combination index, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, hemic and immune systems, Drug Synergism, BET protein, Bromo- and Extra-Terminal protein, Peptide Fragments, Mitochondria, ERMS, embryonal rhabdomyosarcoma, ARMS, alveolar rhabdomyosarcoma, RMS, rhabdomyosarcoma, FCS, fetal calf serum, biological phenomena, cell phenomena, and immunity |
| الوصف: | Highlights • Co-inhibition of BET proteins and anti-apoptotic BCL-2 proteins induces apoptosis in RMS. • JQ1 and BH3-mimetics synergistically induce cell death in RMS. • Cell death is caspase-dependent and displays hallmarks of intrinsic apoptosis. • JQ1/A-1331852-mediated apoptosis is dependent on BIM and NOXA. • JQ1/S638450-mediated apoptosis is dependent on BIM but not NOXA. BH3 mimetics are promising novel anticancer therapeutics. By selectively inhibiting BCL-2, BCL-xL, or MCL-1 (i.e. ABT-199, A-1331852, S63845) they shift the balance of pro- and anti-apoptotic proteins in favor of apoptosis. As Bromodomain and Extra Terminal (BET) protein inhibitors promote pro-apoptotic rebalancing, we evaluated the potential of the BET inhibitor JQ1 in combination with ABT-199, A-1331852 or S63845 in rhabdomyosarcoma (RMS) cells. The strongest synergistic interaction was identified for JQ1/A-1331852 and JQ1/S63845 co-treatment, which reduced cell viability and long-term clonogenic survival. Mechanistic studies revealed that JQ1 upregulated BIM and NOXA accompanied by downregulation of BCL-xL, promoting pro-apoptotic rebalancing of BCL-2 proteins. JQ1/A-1331852 and JQ1/S63845 co-treatment enhanced this pro-apoptotic rebalancing and triggered BAK- and BAX-dependent apoptosis since a) genetic silencing of BIM, BAK or BAX, b) inhibition of caspase activity with zVAD.fmk and c) overexpression of BCL-2 all rescued JQ1/A-1331852- and JQ1/S63845-induced cell death. Interestingly, NOXA played a different role in both treatments, as genetic silencing of NOXA significantly rescued from JQ1/A-1331852-mediated apoptosis but not from JQ1/S63845-mediated apoptosis. In summary, JQ1/A-1331852 and JQ1/S63845 co-treatment represent new promising therapeutic strategies to synergistically trigger mitochondrial apoptosis in RMS. |
| تدمد: | 1476-5586 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8bbac6aac81f4d40d574992bf92415f7Test https://doi.org/10.1016/j.neo.2021.11.012Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8bbac6aac81f4d40d574992bf92415f7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765586 |
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