Research On Pharmacological Mechanism Of Guanasangon E Against Respiratory Cancer Via ERS-Mediated Autophagy And Apoptosis

Respiratory system cancer is one of the most common and dangerous malignant tumors against human health and life in the world.Lung cancer is the most lethal cancer in the world,while the incidence of nasopharyngeal carcinoma ranks eighth among all cancers in China.Nowadays,the medical technology of cancer treatment is developing continuously,however,it still depends on the way of radiotherapy and chemotherapy to control cancer.Due to the lack of clinical symptoms and effective screening procedures,most of lung cancer and nasopharyngeal carcinoma are diagnosed as advanced stage,the total five-year cure rate and survival rate are still very low,and the patients are very painful in the treatment process.Traditional Chinese medicine is a good source of anticancer drugs because of its wide sources of natural compounds and small side effects.It is of great significance in cancer treatment to detect whether the components extracted from traditional Chinese medicine have anticancer activity and analyze the specific pharmacological mechanism of anticancer.Guangsangon E(GSE),a flavonoid compound isolated from leaves of Morus alba L,exhibits significant cytotoxicity against several cancer cells.However,the anti-cancer molecular mechanism of GSE has still been uncleared.In this research,we investigated that GSE induced autophagic cell death and apoptosis in lung cancer cells and induced apoptosis in NPC cells.We observed that GSE inhibited cancer cells proliferation and induced apoptosis in A549 cells.Meanwhile,the up-regulation of autophagosome marker LC3 and increased formation of GFP-LC3 puncta demonstrated the induction of autophagy in GSE-treated cells.Moreover,GSE enhanced the autophagy flux by enhancing lysosomal activity and the fusion of autophagosomes and lysosomes.When autophagy inhibition,GSE-caused cell death was attenuated,termed as "autophagic cell death".Next,we revealed that ER stress was involved in autophagy induction by GSE.GSE activated the ER stress through ROS accumulation,which was blocked in the presence of ROS scavenger NAC.Furthermore,the autophagic cell death could be blocked by ER stress inhibitor(4?8c)or NAC,indicating that GSE-induced autophagic cell death via ROS-mediated ER stress in A549 cells.At the same time,GSE can inhibit the proliferation of CNE-1 and promote the caspase-dependent apoptosis.The autophagy flux increased and LC3B,an autophagy marker protein,upregulates at the same time.The upregulation of GRP78 expression proved that GSE causes protective autophagy to resist apoptosis through CNE-1 endoplasmic reticulum stress.Taken together,we revealed the molecular mechanism of GSE against lung cancer and it has shown potential in the treatment of cancer.Through the study of this subject,the pharmacological mechanism of GSE against human lung cancer cell A549 and human nasopharyngeal carcinoma cell CNE-1 was clarified,which enriched the medicinal value of mulberry leaves,and provided an effective treatment idea and pharmacological research basis for the development of clinical drugs after GSE.