Abstract 2260: c-Myc induced senescence is dependent on transactivation of actin depolymerizing factor (ADF)/cofilin to mediate potent bystander effect

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Oncogene-induced senescence may prevent unlimited proliferation and lead to cell death. This phenomenon is likely to be associated with up-regulation of p53 and p16INK4 tumor suppressor. Morphological transformation is also an important feature of senescence that exhibits enlarged cell volume and flat morphology. In this study, we found that c-Myc was co-upregulated with cofilin-1, an actin-binding protein essential for actin dynamics and morphological maintenance in replicative senescence. Additionally, oxidative stress induced senescent phenotypes also accompanied by up-regulation of both c-myc and cofilin-1. Knockdown of cofilin-1 was sufficient to minimize the cell shapes and senescence associated β-galactosidase marker that was induced by over-expressed c-myc or oxidative stress. Over-expression of cofilin-1 was also sufficient to induce senescence in the absence of p53 and p16INK4, but was unable to influence c-Myc level. On the other hand, over-expression of c-Myc could induce cofilin-1 expression. We next found that c-myc was able to induce the transactivation of cofilin-1 gene according to results of quantitative polymerase chain reaction (qPCR) and luciferase reporter gene assay. Furthermore, the results of ChIP assay provided evidence that c-myc can bind to two proximal E-box elements nearby the transcriptional initiation on cofilin-1 gene promoter. Although c-myc promoted cellular senescence in vitro, the conditional medium from c-myc over-expressing A549 cells accelerated migration and proliferation in separate cultured cells without c-myc over-expression. Knockdown of cofilin-1 also alleviated this bystander effect caused by over-expression of c-myc. Therefore, c-myc oncogene may require cofilin-1 for cell senescence that influences the growth of other tumor cells. Taken together, current data provide evidence that c-myc/cofilin-1 signaling pathway is a novel mechanism on promoting oncogene-induced cellular senescence and tumor progression. Citation Format: Shih-Ting Lin, Cheng-Han Tsai, Yi-Jang Lee, Chia-Chien Lo, Yen-Ting Chou. c-Myc induced senescence is dependent on transactivation of actin depolymerizing factor (ADF)/cofilin to mediate potent bystander effect. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2260. doi:10.1158/1538-7445.AM2014-2260