The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy

Basu, Alakananda

doi:10.1016/j.pharmthera.2021.107943

Cited by 103 publications

(78 citation statements)

References 236 publications

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“…Mcl-1 is a BH3 protein that belongs to the BCL2 family, which controls apoptosis together with Bcl-2, Bcl2-L-10, Bcl-W and Bcl-xL. Mcl-1 has a different structure compared to the other members of the BCL2 family 60 . While ABT263 can efficiently block Bcl-2 and Bcl-xL, it cannot block Mcl-1 60 .…”

Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

et al. 2022

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Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence. Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination. Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy. Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Mcl-1 for their survival. Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2, an established target for senolytic therapy. While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Mcl-1 inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases. These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

et al. 2022

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“…The senolytic agent ABT-737 and its orally bioavailable formulation ABT-263 (navitoclax), which belong to the class of BH3 mimetics, can inhibit Bcl-2, Bcl-W, and Bcl-X L and initiate apoptosis of senescent cells through a mitochondria-dependent pathway (Basu, 2021). The highly potent and selective Bcl-X L inhibitors A-1155462 and A-1331852 have also been proven to have proapoptotic ability but less hematological toxicity than navitoclax (Zhu et al, 2017).…”

Section: Senolyticsmentioning

confidence: 99%

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

Yin

Chen

Wang

et al. 2021

J of Extracellular Vesicle

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Cellular senescence is a persistently hypoproliferative state with diverse stressors in a specific aging microenvironment. Senescent cells have a double-edged sword effect: they can be physiologically beneficial for tissue repair, organ growth, and body homeostasis, and they can be pathologically harmful in age-related diseases. Among the hallmarks of senescence, the SASP, especially SASP-related extracellular vesicle (EV) signalling, plays the leading role in aging transmission via paracrine and endocrine mechanisms. EVs are successful in intercellular and interorgan communication in the aging microenvironment and age-related diseases. They have detrimental effects on downstream targets at the levels of immunity, inflammation, gene expression, and metabolism. Furthermore, EVs obtained from different donors are also promising materials and tools for antiaging treatments and are used for regeneration and rejuvenation in cell-free systems. Here, we describe the characteristics of cellular senescence and the aging microenvironment, concentrating on the production and function of EVs in age-related diseases, and provide new ideas for antiaging therapy with EVs.

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“…Whether senescent cells undergo apoptosis or escape from apoptosis and what determines the fate of senescent cells, these issues have aroused academic controversy. At present, most studies on apoptosis evasion focus on tumors, while studies on endothelial evasion of apoptosis are scarce (8)(9)(10). Due to the low replacement rate of endothelial cells in the human body, it is challenging to regenerate from injury.…”

Section: Introductionmentioning

confidence: 99%

p53 SUMOylation Mediates AOPP-Induced Endothelial Senescence and Apoptosis Evasion

Chen

Liu

Chen

et al. 2022

Front. Cardiovasc. Med.

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The aging of endothelial cells plays a critical role in the development of age-related vascular disease. We established a model of endothelial premature senescence by application of Advanced oxidation protein products (AOPPs) modified bovine serum albumin (AOPP-BSA) in human umbilical vein endothelial cells (HUVECs). This cellular senescence was accompanied with endothelial barrier dysfunction and angiogenesis impairment. It was further revealed that these senescent HUVECs underwent apoptosis evasion and the receptor for advanced glycation endproducts (RAGE) played a role in these processes. The AOPP-induced senescence was regulated by the state of autophagy in HUVECs. We further proved that AOPP-BSA attenuated the autophagy of HUVECs, led to p53 SUMOylation at K386, resulting in endothelial senescence. We also established the animal model of vascular senescence by using ApoE−/− mice fed with high-fat diet plus daily injection of AOPP-BSA to verify the role of p53 SUMOylation in vascular senescence. Combined with intraperitoneal injection of rapamycin, the effect of autophagy on AOPP-induced p53 SUMOylation was also confirmed in vivo. Our data indicates that p53 SUMOylation at K386 plays an important role in AOPP-induced endothelial senescence and apoptosis evasion, suggesting that p53 K386 SUMOylation may serve as a potential therapeutic target in protecting against vascular senescence.

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The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy

Cited by 103 publications

References 236 publications

Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer

Roles of extracellular vesicles in the aging microenvironment and age‐related diseases

p53 SUMOylation Mediates AOPP-Induced Endothelial Senescence and Apoptosis Evasion

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