Abstract 2248: The implication of STAT3 degradation and its mitochondrial functions in cellular senescence

Cellular senescence is a stable growth arrest of the cell cycle considered to be a mechanism of tumor suppression. We have recently described a senescence associated protein degradation or SAPD process that targets many proteins required for tumor progression. The Signal transducer and activator of transcription 3 is one of the targets of SAPD and its downregualtion by RNAi is sufficient to trigger senescence. In the last decade several different functions of STAT3 have been described. Beyond its canonical role as a transcription factor, it has been shown that STAT3 is imported into mitochondria and regulate the activity of the respiratory chain. In this study we want to clarify which function of STAT3 is required to prevent senescence. To do that we have made several mutants of STAT3 affecting different domains of the protein and tested their ability to rescue the senescence response to an anti-Stat3 shRNA. We have found that phosphorylation on residue S727 of STAT3 is important to reestablish proliferation in shSTAT3 induced senescence. Further, transcriptional activity of STAT3 is not required to rescue senescence as a mutant unable to enter the nucleus or the transcriptionally death STAT3 K180A are both able to bypass shSTAT3-induced senescence. Moreover, phosphorylation on Y705 seems not to be important as Y705F STAT3 is also able to reestablish proliferation. All in all, it seems that mitochondrial function of STAT3 is required to prevent senescence since STAT3 S727 phosphorylation is linked to the mitochondrial import of STAT3. Citation Format: Sebastian Igelmann, Xavier Deschenes-Simard, Frederic Lessard, Veronique Bourdeau, Gerardo Ferbeyre. The implication of STAT3 degradation and its mitochondrial functions in cellular senescence. [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 2248. doi:10.1158/1538-7445.AM2014-2248