Abstract B163: Over-expression of STAT-3 induces anoikis resistance, promotes cell migration and metastatic potential in cancer cells.

Abstract

Abstract Anoikis is an anchorage independent cell death. Resistance to anoikis is one of the key features of the metastatic cells. In the current study, we have shown the role of STAT-3 in anoikis resistance in various melanoma and pancreatic cancer cells. Marked anoikis was induced as such in the cells that were grown in anchorage-independent conditions. The melanoma and pancreatic cancer cells that resisted anoikis were observed to have higher rate of migration as compared to the cells that were exposed to anchorage dependent growth, as observed in cell migration and invasion assays. These anoikis resistant cells also had significantly higher expression and phosphorylation of STAT-3 at Tyr 705, than the cells that were attached to the basement membrane. Treatment of these cells with IL-6, a cytokine which phosphorylates STAT-3, prevented the induction of anoikis. STAT-3 inhibitors AG490 and piplartine induced anoikis in a concentration-dependent manner, whereas IL-6 blocked anoikis. Over-expression of STAT-3 by transfection, not only increased the anoikis resistance but also protected cancer cells from piplartine-induced anoikis, confirming the role of STAT-3 in anoikis resistance. On the other hand, silencing STAT-3 decreased the potential of cancer cells to resist anoikis. Furthermore, STAT-3 (-/-) cancer cells were more sensitive to anoikis as well as to the effect of piplartine as compared to STAT-3 (+/+) cells. The STAT-3 (+/+) cells also had enhanced migration potential as compared to STAT-3 (-/-) cells. STAT-3 (-/-) cells and the cells that were treated with PL completely failed to develop tumors when injected subcutaneously in immune-compromised mice. Moreover, these cells also failed to metastasize when injected intravenously. On the other hand, STAT-3 (+/+) cells not only formed aggressive tumors subcutaneously but also highly metastasized when injected intravenously. In summary, our results establish STAT-3 as a critical player that renders anoikis resistance to the cancer cells and enhance their metastasis potential. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B163. Citation Format: Neel Manoj Fofaria, Sanjay K. Srivastava. Over-expression of STAT-3 induces anoikis resistance, promotes cell migration and metastatic potential in cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B163.