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We would like to acknowledge Ministerio de Ciencia, Innovacion y Universidades Grant RTI2018-094533-A-I00 funded by MICIU/AEI/ 10.13039/501100011033 and by "ERDF A way of making Europe"; Grant PID2021-128644OB-I0 << PROYECTOS DEGENERACI & Oacute;N DE CONOCIMIENTO >> funded by MICIU/AEI/ 10.13039/501100011033and by"ERDF/EU"; CELLEX foundation; Jose Carreras Leukaemie-Stiftung grant DJCLS19R/2022; and Agencia de Gestio d'Ajuts Universitaris i de Recerca-Generalitat de Catalunya 2021-SGR-00284. JS acknowledges "Plan Complementario de Biotecnologia aplicada a la Salud", coordinado por el Institut de Bioenginyeria de Catalunya(IBEC) en el marco del Plan de Recuperacion, Transformacion y Resiliencia (C17.I1)-Financiado por la Union Europea-NextGenerationEU". Also, Department of Research and Universities of the Generalitat de Catalunya (2021 SGR 01545). CERCA Programme / Generalitat de Catalunya and Networking Biomedical Research Center(CIBER) of Spain. CIBER is an initiative funded by the VI National R&D & i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and the Instituto deSalud Carlos III (RD16/0006/0012), with the support of the European Regional Development Fund (ERDF).

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HRK downregulation and augmented BCL-xL binding to BAK confer apoptotic protection to therapy-induced senescent melanoma cells

Publicated to:Cell Death And Differentiation. 32 (4): 646-656 - 2025-04-01 32(4), DOI: 10.1038/s41418-024-01417-z

Authors: Alcon, Clara; Kovatcheva, Marta; Morales-Sanchez, Paula; Lopez-Polo, Vanessa; Torres, Teresa; Puig, Susana; Lu, Albert; Samitier, Josep; Enrich, Carlos; Serrano, Manuel; Montero, Joan

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Abstract

Senescent cells are commonly detected in tumors after chemo and radiotherapy, leading to a characteristic cellular phenotype that resists apoptotic cell death. In this study, we used multiple melanoma cell lines, molecular markers, and therapies to investigate the key role of the BCL-2 family proteins in the survival of senescent cells. We first used BH3 profiling to assess changes in apoptotic priming upon senescence induction. Unexpectedly, not all cell types analyzed showed a decrease in apoptotic priming, BIM was downregulated, there was variability in BAX expression and BAK remained constant or increased. Therefore, there was not a clear pattern for pro-survival adaptation. Many studies have been devoted to find ways to eliminate senescent cells, leading to one of the most studied senolytic agents: navitoclax, a promiscuous BH3 mimetic that inhibits BCL-2, BCL-xL and BCL-W. While it is known that the BCL-2 family of proteins is commonly upregulated in senescent cells, the complexity of the apoptotic network has not been fully explored. Interestingly, we found distinct protein expression changes always leading to a BCL-xL mediated pro-survival adaptation, as assessed by BH3 profiling. When analyzing potential therapeutic strategies, we observed a stronger senolytic activity in these melanoma cell lines when specifically targeting BCL-xL using A-1331852, navitoclax or the PROTAC BCL-xL degrader DT2216. We found that the sensitizer protein HRK was systematically downregulated when senescence was induced, leading to an increased availability of BCL-xL. Furthermore, we identified that the main apoptotic inhibition was shaped by BCL-xL and BAK binding increase that prevented mitochondrial permeabilization and apoptosis. To our knowledge, this is the first time that the molecular basis for BCL-xL anti-apoptotic adaptation in senescence is described, paving the way for the development of new molecules that either prevent HRK downregulation or displace BCL-xL binding to BAK to be used as senolytics.

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