肺がん細胞の senolysis とferroptosis において 細胞質 p21Cip1/Waf1 は防御的に作用する

概要

When cancer cells are treated with anticancer drugs, some of them mitigate DNA damage
by stopping or slowing down their cell cycle, a process known as cellular senescence. Recently,
some studies have shown that therapy-induced senescent (TIS) cancer cells produce several
cytokines and factors, known as a senescence-associated secretary phenotype (SASP), which
promote recurrence and metastasis of residual cancer cells. Therefore, TIS has been considered a
major hurdle that must be overcome to improve the prognosis of cancer patients receiving
anticancer therapies.
The cyclin-dependent kinase (CDK) inhibitors p16Ink4a and p21Cip1/Waf1 are two key
molecules involved in cellular senescence. TIS is accompanied by increasing expression of these
CDK inhibitors. In terms of human adenocarcinoma, inactivation of the p16 gene is often
observed, suggesting that p21 plays a crucial role in the survival of TIS cancer cells. In addition,
p21 is involved in various cell functions and can work as a tumor suppressor as well as a tumor
promoter. Despite its role in promoting apoptosis, p21 prevents apoptosis in cancer cells in
response to anticancer therapies.
A new approach of selectively removing senescent cells known as senolysis has been
proposed. Senolytic drugs can preferentially induce cell death in senescent cancer cells.
ABT-263 (navitoclax) is one such drug that was identified as an inhibitor against Bcl-2, Bcl-xL,
and Bcl-w. In this study, we examined the senolytic effects of ABT-263, as well as its analogue
ABT-737, on TIS human lung adenocarcinoma cells. In addition, we found that pemetrexed
(PEM) alone induced ferroptosis, a new type of cell death, in lung adenocarcinoma cells. ...