Enhanced extrinsic apoptosis of therapy-induced senescent cancer cells using a death receptor 5 (DR5) selective agonist.

Abel Soto-Gamez,Wim Quax,Lorina Seras,Xinyu Zhou,Marco Demaria,Yizhou Wang

doi:10.1016/j.canlet.2021.10.038

Abstract

Genotoxic agents are widely used anti-cancer therapies because of their ability to interfere with highly proliferative cells. An important outcome of these interventions is the induction of a state of permanent arrest also known as cellular senescence. However, senescent cancer cells are characterized by genomic instability and are at risk of escaping the growth arrest to eventually facilitate cancer relapse. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) signals extrinsic apoptosis via Death Receptors (DR) 4 and 5, while Decoy Receptors (DcR) 1 and 2, and Osteoprotegerin (OPG) are homologous to death receptors but incapable of transducing an apoptotic signal. The use of recombinant TRAIL as an anti-cancer strategy in combination with chemotherapy is currently in development, and a major question remains whether senescent cancer cells respond to TRAIL. Here, we show variable sensitivity of cancer cells to TRAIL after senescence induction, and upregulation of both pro-apoptotic and anti-apoptotic receptors in therapy-induced senescent cancer cells. A DR5-selective TRAIL variant (DHER), unable to bind to DcR1 or OPG, was more effective in inducing apoptosis of senescent cancer cells compared to wild-type TRAIL. Importantly, no apoptosis induction was observed in non-cancerous cells, even at the highest concentrations tested. Our results suggest that targeting DR5 can serve as a novel therapeutic strategy for the elimination of therapy-induced senescent cancer cells.

Highlights

Cellular senescence is a stable cell cycle arrest that arises in response to various stressors
We initially focused on triple negative breast cancer cell lines MDAMB-231 and MDA-MB-436, which are sensitive to tumor necrosis factor related apoptosis inducing ligand (TRAIL) [31]
Therapy-induced senescence (TIS) was prompted by one of the most common chemotherapeutic agent used for breast cancer treatment, the anthracyclin doxorubicin [32]. 8 days after treatment, breast cancer cells displayed typical markers of senescence such as high senescence-associated β-galactosidase (SA-β-gal) activity (Fig. 1A and B and Fig. S1A), reduced proliferation measured by EdU incorporation (Fig. 1A and C), increased expression of cyclin-dependent kinase in hibitor p21Cip1 (p21) and different senescence-associated secretory phenotype (SASP) factors and decreased expres sion of LaminB1 (LMNB1)

Summary

Introduction

Cellular senescence is a stable cell cycle arrest that arises in response to various stressors. Structural and functional changes influenced by multiple variables, including type of stressor, time elapsed, and tissue or cell type. Cellular senescence represents an important barrier to tumorigenesis by limiting the growth of oncogenic cells. In clinical settings both chemotherapy and radiation are widely used as anti-cancer therapies for their ability to induce cell cycle arrest and apoptosis in cancer cells [1]. The response of senescent cancer cells to current senolytic approaches remains highly variable [5]

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Results

Conclusion