Fig. 9. Schematic diagram.
Ursolic acid (UA) plus 3,3’-diindolylmethane (DIM) combination treatment can induce apoptosis by promoting cleaved-PARP and caspase-9, increasing the G1 phase by upregulating CDK4, CDK6, and Cyclin D1 protein expression, and inhibiting migration by regulating E-cadherin, MMP-9, and MMP-13 in esophageal squamous cell carcinoma (ESCC). UA plus DIM combination treatment lowered p-Akt and p-Gsk-3β expression in ESCC. UA plus DIM combination activated the Hippo signaling pathway leading to the inhibition of YAP de-phosphorylation and nuclear translocation and suppression of its downstream gene CTGF further restrained cell growth in ESCC. UA and DIM combination treatment induced the Hippo pathway activation by inhibiting the PI3K/Akt pathway in ESCC. UA plus DIM combination treatment can induce YAP inhibition by conversely inhibiting the PI3K/Akt pathway through up-regulated PTEN. UA plus DIM stimulated a feedback loop between the PI3K/Akt signaling pathway and Hippo signaling pathways in ESCC.
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