Abstract B13: Cancer metabolism sensitizes metformin treatment by targeting the Hippo-YAP/TAZ pathway

Abstract

Abstract The biologic significance and deregulation of the Hippo pathway during organ growth and tumorigenesis have received a surge of interest in the past decade. The Hippo pathway core kinases, MST1/2 and LATS1/2, are tumor suppressors that inhibit the oncogenic nuclear function of YAP/TAZ and TEAD. Dysregulation of Hippo pathway leads to tumorigenesis via hyperactivation of YAP/TAZ. In this study, we focused on how differential metabolic stress response (DMSR) between normal and cancer cells, such as the Warburg effect, could synergize with the anticancer effect of metformin to regulate the Hippo pathway. Surprisingly, metformin treatment combined with low glucose concentration activates the Hippo pathway, which induces YAP/TAZ phosphorylation, loss of cell adhesion, and cell death in a cancer cell-specific manner. Using CRISPR KO cells, we show that YAP/TAZ inhibition by metformin in combination with glucose restriction is AMPK and p38 MAPK-independent, but Hippo-dependent. Therefore, these results demonstrate that DMSR-based glucose restriction and metformin cotreatment can be a novel therapeutic approach to treat cancer via inhibition of cancer cell-specific YAP/TAZ activity. Citation Format: Jae Hyung Park, Hyun Woo Park. Cancer metabolism sensitizes metformin treatment by targeting the Hippo-YAP/TAZ pathway [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B13.