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

Abstract

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 membrane-stable mutant form CD40L (CD40L-M) to explore tumor growth and cellular senescence in CD40-positive NSCLC cells. We found that CD40L-M-expressing cells had senescent characteristics, including reduced cell proliferation and enlargement, increased SA-β-gal staining activity, and overexpression of several cell cycle regulators p53 and p21. In addition, expression of GATA4 was restored, and the NF-κB signaling pathway was activated in the CD40L-M-induced senescent cells. Mechanistic analyses revealed that CD40L-M expression triggered the ATM/Chk2 DNA damage response, which mediated cell senescence and GATA4 activation. Knockdown of GATA4 reversed CD40L-M-induced senescence and decreased NF-κB activity. Thus, CD40L-M contributes to induction of cell senescence in CD40-positive NSCLC cells, and GATA4 is a switch to activate the NF-κB pathway, which is positively regulated by DNA damage response (DDR) signaling kinases. Collectively, CD40L-M-induced senescence may be a barrier to the growth of lung cancer cells.