Metformin attenuates PD-L1 expression through activating Hippo signaling pathway in colorectal cancer cells

• Published in: American journal of translational research Vol. 11; no. 11; pp. 6965 - 6976
• Main Authors: Zhang, Jun-Jie, Zhang, Qiu-Shi, Li, Zi-Qian, Zhou, Jia-Wang, Du, Jun
• Format: Journal Article
• Language: English
• Published: United States e-Century Publishing Corporation 01.01.2019
• Subjects: Original; PD-L1; Metformin; colorectal carcinoma; Hippo signaling pathway
• ISSN: 1943-8141; 1943-8141

Programmed cell death ligand 1 (PD-L1) is a key suppressor of the cytotoxic immune response. In colorectal carcinoma (CRC), PD-L1 expression results in immune escape and poor prognosis. Extensive researches suggested that metformin had a potential efficacy of enhancing anti-tumor immune response in different types of cancer. However, the detail mechanisms underlying the efficacy in CRC are unclear. Here, we showed that metformin decreases PD-L1 and YAP1 expression and . After silencing or inhibiting YAP1 expression by Verteporfin (VP), the inhibitor of YAP1, the expression of PD-L1 were decreased in protein level in CRC cells. Furthermore, metformin directly phosphorylated YAP1 and restricted YAP1 to entry in the nucleus, so that PD-L1 was reduced via western blot and immunofluorescence assays in SW480 and HCT116 cells. Finally, subcutaneous xenotransplanted tumor models of HCT116 cells were established in BALB/c nude mice. Compared with the control group, PD-L1 and YAP1 expressions in tumor tissues, detected by immunohistochemistry, were reduced in the group of metformin treatment. These findings illuminate a new regulatory mechanism, metformin activates Hippo signaling pathway to regulate PD-L1 expression and suggests that metformin has the possibility to increase the efficacy of immunotherapy in human CRC.