Breaking senescence restriction: MAFK-AREG axis promotes NSCLC cells to resist doxorubicin

Musculoaponeurotic fibrosarcoma oncogene homolog K (MAFK) and amphiregulin (AREG) promote non-small cell lung cancer (NSCLC) progression. However, whether MAFK regulates AREG to mediate the escape of NSCLC cells from doxorubicin (DOX)-induced senescence remains unclear. In the present study, chemotherapy-modulated senescence-related genes were identified through bioinformatics analysis. Human non-small cell lung adenocarcinoma cell lines (A549 and PC-9 cells) were treated with DOX to generate persistent A549 cells (PACs) and persistent PC-9 cells (PPCs). The expression levels of MAFK, AREG and the senescence-associated protein p21 wild-type p53-activated fragment 1 (p21waf1) were evaluated using western blotting and reverse transcription-quantitative PCR. Senescence-associated β-galactosidase staining and colony formation assays were performed to assess cellular senescence and proliferation. The proportions of senescent and proliferating PACs and PPCs were quantified using flow cytometry. A chromatin-immunoprecipitation assay was performed to examine the regulatory association between MAFK and AREG. AREG was associated with cellular senescence, as demonstrated by changes in senescence markers. In A549 and PC-9 cells, DOX treatment upregulated p21waf1 expression, induced senescence, inhibited proliferation and downregulated both MAFK and AREG expression. By contrast, PACs/PPCs exhibited enhanced proliferation alongside elevated MAFK and AREG levels. PACs and PPCs comprised 60-70% senescent cells and 30-40% proliferating cells. MAFK bound directly to the AREG promoter region. In addition, MAFK overexpression reversed the suppressive effect of AREG knockdown on the proliferation of A549 and PC-9 cells. Collectively, MAFK enabled NSCLC cells to escape DOX-induced senescence by upregulating AREG and facilitated cell proliferation upon DOX treatment.