Enhanced extrinsic apoptosis of therapy-induced senescent cancer cells using a death receptor 5 (DR5) selective agonist
Soto-Gamez, A. et al. (2022) Enhanced extrinsic apoptosis of therapy-induced senescent cancer cells using a death receptor 5 (DR5) selective agonist. Cancer Lett. 525, 67–75. DOI: 10.1016/j.canlet.2021.10.038
Cellular senescence is a state of cell-cycle arrest that occurs typically in response to external stress factors. Anti-cancer therapies, including chemotherapy and radiation, are often directed toward inducing senescence or programmed cell death (apoptosis) in cancer cells. However, senescent cells are characterized by genomic instability, and they can escape from apoptosis, causing cancer relapse. These senescent cells are resistant to apoptosis-inducing factors, including cytotoxic drugs, via pathways involving so-called death receptors that recruit adapter proteins and caspases. Most death receptors belong to the tumor necrosis factor (TNF) family.
The TNF-related apoptosis inducing ligand (TRAIL) signals extrinsic apoptosis via death receptors, and current anti-cancer strategies are investigating its use as a therapeutic agent. This study examined the sensitivity of senescent cells to TRAIL after exposure to genotoxic stress. Cancer cells showed variable sensitivity to TRAIL after induction of senescence, while expression of both pro- and anti-apoptotic receptors was elevated. The researchers showed that a TRAIL variant with selectivity for death receptor 5 (DR5) was more effective at inducing apoptosis than wild-type TRAIL. No apoptosis induction was observed in noncancerous cells, even at the highest concentrations tested. Therefore, the DR5-selective TRAIL variant shows promise as a novel anticancer agent to eliminate therapy-induced cancer cell senescence.
Keywords: senescence, TRAIL, apoptosis, cancer therapy, caspase
