Abstract
Sitagliptin is an emerging oral hypoglycemic agent that inhibits the development of a wide variety of tumors. Current researches indicate that the abnormal activation of Yes‐associated protein (YAP) promotes the proliferation and poor prognosis of multiple tumors. However, the ability of sitagliptin to regulate YAP and its effects on gastric cancer (GC) cells remain unclear. Here, we first showed that sitagliptin inhibited the proliferation of GC cells, and this inhibition was regulated by Hippo pathway. Sitagliptin phosphorylated YAP in a large tumor suppressor homolog‐dependent manner, thereby inhibiting YAP nuclear translocation, and promoted YAP cytoplasm retention. This inhibition can be blocked by adenosine 5′‐monophosphate‐activated protein kinase (AMPK). Moreover, sitagliptin could reduce the expression of tumor‐testis antigen Melanoma‐associated antigen‐A3 through YAP. In conclusion, sitagliptin may have a potential inhibitory effect on GC by AMPK/YAP/melanoma‐associated antigen‐A3 pathway.
Highlights
Diabetes is a chronic metabolic disease with an increasing prevalence
This study demonstrates that sitagliptin exerts an anticancer function through AMPK/Yes-associated protein (YAP)/Melanoma-associated antigen-A3 (MAGE-A3) signaling axis and provides new options for the treatment of gastric cancer (GC)
The results showed that Connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61) were downregulated by sitagliptin at the mRNA level (Figure 2G)
Summary
Diabetes is a chronic metabolic disease with an increasing prevalence. An estimated 642 million people all over the world aged between 20 and 79 years old will develop in diabetes by 2040.1 Recently, growing epidemiological evidence has shown an increased risk of gastric cancer (GC) among diabetic patients. It is known that tumor antigens can induce a strong specific immune response in the body, which can provide new ideas for antitumor treatment.[18] Among many tumor antigens, more and more tumor-testis antigens have attracted the attention of researchers. Such antigens include sal-like gene family, melanoma-associated antigen gene family, and synovial sarcoma X breakpoint gene family,[18,19] etc. The current researches on MAGE-A3 indicate that MAGE-A3 can promote tumor cell proliferation and affect tumor prognosis by regulating multiple apoptotic proteins.[22] we hypothesized that YAP/ MAGE-A3 may be a new target for sitagliptin. This study demonstrates that sitagliptin exerts an anticancer function through AMPK/YAP/MAGE-A3 signaling axis and provides new options for the treatment of GC
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