Abstract 5204: PP2A- STAT3 pathway mediates suspension survival in colon cancer stem cells

Abstract

Abstract Cancer stem or initiating cells (CSCs) which share similarity with normal stem cells are a small population of cells in tumor with the abilities of self-renewal, multi- potent differentiation, and tumor initiation. CSCs also contribute to the resistance of tumor to chemotherapy or irradiation therapy. Therefore, targeting CSCs could be a hopeful way in treating cancer. Involvement of constitutive phosphorylation of STAT3 at Tyr705 in tumorigenesis of CSCs was implicated in many types of cancers. However, the role of Ser727 phosphorylation in STAT3 activation and CSCs tumorigenesis remains unknown. In this study, we are trying to figure out whether Ser727 phosphorylation of STAT3 plays a role in the characteristic properties of colon CSCs. Efforts will also be made to shed light on the upper signaling pathway and downstream targets of Ser727 phosphorylation of STAT3. Our preliminary data demonstrate enriched CSCs increase in the capacity for suspension survival both in vitro and in vivo. After enrichment of CSC population by spheroid culture, the phosphorylation of STAT3 at Ser727 but not Tyr705 was increased and localized at nucleus. The increase of Ser727 activation is also associated with down-regulation of PP2A activity, a serine/threonine phosphatase candidate of STAT3. We further proved PP2A formed immunoprecipitated complex with STAT3 and regulated STAT3 activation at Ser727 by treating the cells with PP2A inhibitor in normal culture or PP2A activator in spheroid culture. Overexpression of wild-type PP2A or Ser727 point mutated STAT3 reduced the survival ability in CSC. In contrast, knock down of PP2A activity or gain of function mutation at Ser727 of STAT3 increased the survival ability in nCSC. Taken together, our current data indicate enriched CSCs increased the capacity of suspension survival through the activation of PP2A-STAT3 pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5204. doi:10.1158/1538-7445.AM2011-5204