DNA damage induced by human CD40 ligand mutant promotes senescence and induces demethylation of GATA4 in lung cancer.

作者：Li Yue; Wei Yunyan; Yuan Weiwei; Huang Qiqing; Zhao Yaya; Zhao Weihong; Xu Wei; Wu Jianqing

来源：Oncology Reports, 2018.

DOI：10.3892/or.2018.6310

The ligand of CD40, known as CD154 or CD40L, is the key to immunostimulatory and anticancer activity, but how CD40L affects cellular senescence is unclear. Thus, we studied a membranestable mutant form CD40L (CD40LM) to explore tumor growth and cellular senescence in CD40positive NSCLC cells. We found that CD40LMexpressing cells had senescent characteristics, including reduced cell proliferation and enlargement, increased SAbetagal staining activity, and overexpression of several cell cycle regulators p53 and p21. In addition, expression of GATA4 was restored, and the NFkappaB signaling pathway was activated in the CD40LMinduced senescent cells. Mechanistic analyses revealed that CD40LM expression triggered the ATM/Chk2 DNA damage response, which mediated cell senescence and GATA4 activation. Knockdown of GATA4 reversed CD40LMinduced senescence and decreased NFkappaB activity. Thus, CD40LM contributes to induction of cell senescence in CD40positive NSCLC cells, and GATA4 is a switch to activate the NFkappaB pathway, which is positively regulated by DNA damage response (DDR) signaling kinases. Collectively, CD40LMinduced senescence may be a barrier to the growth of lung cancer cells.