Page 100 - D. Cancer biology

[D. Cancer biology-65]

Cancer metabolism sensitizes metformin treatment by

targeting the Hippo-YAP/TAZ Pathway

Jae Hyung Park¹, Hyun Woo Park¹˙*

¹Biochemistry, Yonsei University, Seoul 03722, Republic of Korea

The biological 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 inhibits 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 anti-cancer
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-basedglucose restriction and metformin co-treatment can be a novel therapeutic
approach to treat cancer via inhibition of cancer cell-specific YAP/TAZ activity.