Abstract 4305: AMPK-RUNX2-mTORC2 axis involved in EMT of MDA-MB-231 breast cancer cells

Metformin is one of the most widely used biguanides for the treatment of type 2 diabetes, whose role as a potent anti-cancer drug has emerged in recent times. Its function as an anti-tumor agent is attributed to its ability to inhibit mTORC1, which is a key player in regulating cell proliferation. However, the use of metformin as an anti-cancer drug is hampered by several limitations. Hence, in order to elucidate the detailed mechanistic properties of metformin in cell growth and metastasis, we investigated the effect of metformin on mTORC2 activity in MDA-MB-231 cells. We report a novel mechanism by which metformin can increase the activity of mTORC2 in a Runx2-dependent fashion, which requires AMPK mediated stabilization of RUNX2. Furthermore, we found that mTORC2 and RUNX2 have a feed forward relation whereby the knockdown of rictor, a key component in activating mTORC2, resulted in loss of RUNX2 through GSK3-β-mediated ubiquitination of RUNX2. Since both mTORC2 and RUNX2 have been found to be involved in activating the EMT, metformin treatment may contribute to this activation by stabilizing AMPK-RUNX2-mTORC2 axis. These results demonstrate that metformin-induced mechanisms can influence metastasis even if they inhibit cell growth, but the genetic heterogeneity of the malignancy may govern cell fate. Citation Format: Aramati Bindu Reddy, Meher B. Gayatri, Suresh Chava. AMPK-RUNX2-mTORC2 axis involved in EMT of MDA-MB-231 breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4305.