Senolytic Properties of DR5-Selective TRAIL in Pancreatic Cancer Cell Lines

Pancreatic adenocarcinoma is one of the most aggressive cancers. Its treatment relies on conventional chemotherapy agents; particularly gemcitabine. Chemotherapy is known to induce cell cycle arrest and the development of a senescent phenotype in tumor cells. The accumulation of senescent cells limits tumor proliferation, followed by the secretion of factors of the senescence-associated secretory phenotype promoting malignancy in the tumor microenvironment and metastasis. This makes the search for drugs suitable for senolytic therapy highly relevant. This study explored the senolytic properties of a DR5 receptor-selective mutant variant of the antitumor cytokine TRAIL DR5-B in human pancreatic cancer cell lines, after prolonged co-incubation with gemcitabine or doxorubicin. In the MIA PaCa-2 and PANC-1 cell lines, both drugs significantly increased β-galactosidase activity and the expression of senescence markers, such as the cell cycle inhibitors p21 and p27; DR5-B effectively suppressed cell viability after chemotherapy treatment. In the BxPC-3 cell line, the drugs did not induce senescence and DR5-B cytotoxicity was virtually unchanged. Some features of senescence were observed in AsPC-1 cells; however, these cells remained resistant to DR5-B, presumably due to cFLIP overexpression. Hence, the DR5-B protein shows promise as a senolytic agent for the treatment of certain types of pancreatic adenocarcinoma.