Glibenclamide Inhibited Non-Small Cell Lung Carcinoma Through Up-Regulation Of KLF4 Expression

Lung cancer is one of the major malignant tumors threatening people’s life. Its morbidity and mortality remains the first in cancer related deaths. Although the early diagnosis and treatment of lung cancer have developed greatly, most patients are diagnosed at advanced stage. Therefore, chemotherapy and targeted cancer therapy remains important in the treatment of lung cancer. In our contontry, the morbidity and mortality of lung cancer increased every year. Therefore, identifying new target and developing effective anti-cancer drugs are urgently needed.In recent years, it has been reported that diabetic patients have the higher risk of developing cancer, and oral hypoglycemic drugs, such as metformin, decreased the cancer risk of type II diabetes. Moreover, metformin have been proved to have anticancer effect. Some other studies reported that sulfonylureas, such as glibenclamide reduced the risk of cancer as well. It supresses cell growth, invasion, metastasis, and induction of apoptosis in gastric cancer, breast cancer, hepatoma carcinoma, and ovarian cancer. Currently, fotits effect and mechanism on lung cancer are unknown.Kruppel-like Factor 4 (KLF4), a zinc finger-type transcription factor, is important for many physiologic processes, including proliferation, differentiation, and apoptosis. It has been found that the expression of KLF4 decreased in gastric cancer, colon cancer, esophageal squamous carcinoma, bladder cancer, prostate cancer, and B corpuscle lymphoma, while increased in oral squamous cell carcinomas and breast cancer. It has been reported to be an oncogene or a tumor supressor in different types of cancers.Currently, for its role and mechanism in lung cancer are quite unclear.In this study, we found that glibenclamide inhibited the growth of non-small cell lung cancer cells (NSCLCs), including A549, H460, Calu-1, and H157 cells, epithelial-mesenchymal transition (EMT), and migration. As well, glibenclamide increased the expression of KLF4. Then, we found that knockdown of KLF4 expression promotes cell growth, EMT and migration, indicating that KLF4 functions as a tumor suppressor in NSCLCs. Moreover, Then we demonstrated that in NSCLCs knockdown of KLF4 expression partially reversed the effects of glibenclamide, such as inhibition of cell growth, EMT and migration.Finally, glibenclamide inhibited the growth of A549 and H460 tumors in parallel with upregulation of KLF4 expression in a xenograft nude mouse model. Our results suggest that glibenlcamide inhibits the growth, EMT, and migration of NSCLC through upregulation of KLF4 expression. Our work clarifys the anti-tumor effect and mechanism of glibenclamidein lung cancer, and providing new strategy for cancer therapy.