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Ouabain and chloroquine trigger senolysis of BRAF‐V600E‐induced senescent cells by targeting autophagy
Abstract
The expression of BRAF‐V600E triggers oncogene‐induced senescence in normal cells and is implicated in the development of several cancers including melanoma. Here, we report that cardioglycosides such as ouabain are potent senolytics in BRAF senescence. Sensitization by ATP1A1 knockdown and protection by supplemental potassium showed that senolysis by ouabain was mediated by the Na,K‐ATPase pump. Both ion transport inhibition and signal transduction result from cardioglycosides binding to Na,K‐ATPase. An inhibitor of the pump that does not trigger signaling was not senolytic despite blocking ion transport, demonstrating that signal transduction is required for senolysis. Ouabain triggered the activation of Src, p38, Akt, and Erk in BRAF‐senescent cells, and signaling inhibitors prevented cell death. The expression of BRAF‐V600E increased ER stress and autophagy in BRAF‐senescent cells and sensitized the cell to senolysis by ouabain. Ouabain inhibited autophagy flux, which was restored by signaling inhibitors. Consequently, we identified autophagy inhibitor chloroquine as a novel senolytic in BRAF senescence based on the mode of action of cardioglycosides. Our work underlies the interest of characterizing the mechanisms of senolytics to discover novel compounds and identifies the endoplasmic reticulum stress‐autophagy tandem as a new vulnerability in BRAF senescence that can be exploited for the development of further senolytic strategies.
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Bafilomycin A1 disrupts cytoprotective autophagy in senescent cells, leading to accumulation of damaged mitochondria and apoptotic cell death.
“bafilomycin A1 disrupts cytoprotective autophagy in SnCs, leading to accumulation of damaged mitochondria and apoptotic cell death51.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [51]
The Results section (‘Autophagy inhibitors are senolytic in BRAF senescence’; page unavailable) reports that bafilomycin A1 was senolytic in BRAF-V600E-induced senescent fibroblasts, though less potent than chloroquine. The Discussion reports bafilomycin A1-induced apoptosis in therapy-induced senescent mouse lymphomas. Our copy does not report accumulation of damaged mitochondria, and these findings do not establish the stated mechanism across senescent cells generally. (LLM, conf=0.87)
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Cites
Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C. M., Adams, P. D., Adeli, K., et al. (2016) · Autophagy · doi:10.1080/15548627.2015.1100356 · Cited by 5,894
Guidelines for the use and interpretation of assays for monitoring autophagy
Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., et al. (2012) · Autophagy · doi:10.4161/auto.19496 · Cited by 3,996
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,584 · cited 4×
“Depending on the cell type and the inducing stressor, senescent cells rely on various survival mechanisms to resist apoptosis, such as ephrin signaling or changes in BCL2 family protein expression patterns (Soto- Gamez et al., 2019; Yosef et al., 2016; Zhu et al., 2015).”
BackgroundInfluentialBRAFE600-associated senescence-like cell cycle arrest of human naevi
Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S. (2005) · Nature · doi:10.1038/nature03890 · Cited by 2,160
Cellular senescence mediates fibrotic pulmonary disease
Schafer, M. J., White, T. A., Iijima, K., Haak, A. J., Ligresti, G., Atkinson, E. J., Oberg, A. L., Birch, J., Salmonowicz, H., Zhu, Y., et al. (2017) · Nature Communications · doi:10.1038/ncomms14532 · Cited by 1,613 · cited 1×
“…senolytic treatment so far is the combination of dasatinib and quercetin, which in mice was shown to delay the onset of aging and to alleviate osteoporosis, idiopathic pulmonary fibrosis (IPF), and Alzheimer's disease (Farr et al., 2017; Musi et al., 2018; Schafer et al., 2017; Zhu et al., 2015).”
BackgroundHickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.08.069 · Cited by 1,383 · cited 1×
“Senolytics recently entered the clinic for pilot human trials in IPF and diabetic kidney disease (Hickson et al., 2019; Justice et al., 2019).”
BackgroundSenolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study
Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Hashmi, S. K., Prata, L., Masternak, M. M., Kritchevsky, S. B., Musi, N., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2018.12.052 · Cited by 1,261 · cited 1×
“Senolytics recently entered the clinic for pilot human trials in IPF and diabetic kidney disease (Hickson et al., 2019; Justice et al., 2019).”
BackgroundAutophagy mediates the mitotic senescence transition
Young, A. R. J., Narita, M., Ferreira, M., Kirschner, K., Sadaie, M., Darot, J. F. J., Tavaré, S., Arakawa, S., Shimizu, S., Watt, F. M., et al. (2009) · Genes & Development · doi:10.1101/gad.519709 · Cited by 1,078
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL
Yosef, R., Pilpel, N., Tokarsky-Amiel, R., Biran, A., Ovadya, Y., Cohen, S., Vadai, E., Dassa, L., Shahar, E., Condiotti, R., et al. (2016) · Nature Communications · doi:10.1038/ncomms11190 · Cited by 1,032
Novel therapeutic applications of cardiac glycosides
Prassas, I., & Diamandis, E. P. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2682 · Cited by 673
Tau protein aggregation is associated with cellular senescence in the brain
Musi, N., Valentine, J. M., Sickora, K. R., Baeuerle, E., Thompson, C. S., Shen, Q., & Orr, M. E. (2018) · Aging Cell · doi:10.1111/acel.12840 · Cited by 595
Synthetic lethal metabolic targeting of cellular senescence in cancer therapy
Dörr, J. R., Yu, Y., Milanovic, M., Beuster, G., Zasada, C., Däbritz, J. H. M., Lisec, J., Lenze, D., Gerhardt, A., Schleicher, K., et al. (2013) · Nature · doi:10.1038/nature12437 · Cited by 541
Identification and characterization of Cardiac Glycosides as senolytic compounds
Triana-Martínez, F., Picallos-Rabina, P., Da Silva-Álvarez, S., Pietrocola, F., Llanos, S., Rodilla, V., Soprano, E., Pedrosa, P., Ferreirós, A., Barradas, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12888-x · Cited by 384
Cardiac glycosides are broad-spectrum senolytics
Guerrero, A., Herranz, N., Sun, B., Wagner, V., Gallage, S., Guiho, R., Wolter, K., Pombo, J., Irvine, E. E., Innes, A. J., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0122-z · Cited by 359 · cited 2×
“The senolytic catalog later grew to include notably BH3 mimetics (Yosef et al., 2016; Zhu et al., 2016), HSP90 inhibitors (Fuhrmann- Stroissnigg et al., 2017), and cardioglycosides (Guerrero et al., 2019; Triana- Martínez et al., 2019).”
BackgroundCorazzari, M., Rapino, F., Ciccosanti, F., Giglio, P., Antonioli, M., Conti, B., Fimia, G. M., Lovat, P. E., & Piacentini, M. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.183 · Cited by 162
Maddodi, N., Huang, W., Havighurst, T., Kim, K., Jack Longley, B., & Setaluri, V. (2010) · Journal of Investigative Dermatology · doi:10.1038/jid.2010.26 · Cited by 80
Flagged first, then by citations
Research works printed but not linked: 29
- 10.1002/prp2.505 · DOI
- 10.1038/s41598-018-29995-2 · DOI
- 10.1007/s00280-009-0929-5 · DOI
- 10.1007/s00018-009-9018-5 · DOI
- Carvalho C., 2019, Glucocorticoids delay RAF‐induced senescence promoted by EGR1, Journal of Cell Science, 132, 10.1242/jcs.230748 · DOI
- 10.3389/fphys.2017.00371 · DOI
- 10.3390/molecules22060990 · DOI
- 10.1038/nm.4385 · DOI · Paper page
- 10.1038/s41467-017-00314-z · DOI · Paper page
- 10.4161/auto.28594 · DOI
- 10.1016/j.tcb.2018.02.001 · DOI · Paper page
- 10.1038/onc.2011.481 · DOI
- 10.14348/molcells.2017.2279 · DOI
- 10.1016/j.redox.2019.101337 · DOI
- 10.4161/auto.27163 · DOI
- 10.1172/JCI70454 · DOI · Paper page
- 10.1038/s41598-020-61920-4 · DOI
- 10.1016/j.vascn.2018.09.001 · DOI
- 10.1016/j.ebiom.2019.06.049 · DOI · Paper page
- 10.18632/aging.101633 · DOI · Paper page
- 10.1016/j.jaad.2017.06.149 · DOI
- 10.1016/j.mrrev.2020.108321 · DOI
- 10.1056/NEJMoa1502583 · DOI
- 10.1016/j.jmb.2019.05.036 · DOI · Paper page
- 10.1091/mbc.E05-08-0735 · DOI
- 10.1158/0008-5472.CAN-13-2939 · DOI · Paper page
- 10.1021/bi4011804 · DOI
- 10.1124/mol.110.063974 · DOI
- 10.1111/acel.12445 · DOI · Paper page
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Sorted by citations
Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming
Zhang, W., Song, S., Zhang, Y., Pan, Y., Hu, D., & Wang, Y. (2026) · npj Aging · doi:10.1038/s41514-026-00355-z · Cited by 6
Metadata
- Authors
- L’Hôte, V., Courbeyrette, R., Pinna, G., Cintrat, J., Le Pavec, G., Delaunay‐Moisan, A., Mann, C., & Thuret, J.
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2021-08-06
- Volume
- 20
- Issue
- 9
- ISSN
- 1474-9718
- 1474-9726
- PMC
- PMC8564827
- Cited by
- 37
- References
- 17
- Language
- en
- Funders
- Fondation ARC pour la Recherche sur le Cancer
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