melitten and Pancreatic-Neoplasms

Topics: bcl-2-Associated X Protein; Humans; Melitten; Pancreatic Neoplasms; Phospholipids; Raloxifene Hydrochloride

Long non-coding RNAs (lncRNAs) play crucial roles in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC). Previously, we found that melittin treatment suppressed PDAC tumor growth. However, it is unclear whether lncRNAs have any role in the melittin-induced suppression of PDAC. In this study, we used microarray data to identify 844 lncRNAs that were significantly differentially expressed in response to melittin treatment. Of these lncRNAs, we focused on the lncRNA NONHSAT105177, which had about a 22-fold increase in expression with melittin treatment. We found that melittin treatment increased NONHSAT105177 expression in PDAC cell lines but not in normal pancreatic ductal epithelial cell line. NONHSAT105177 expression was significantly lower in PDAC cancer tissues than in adjacent noncancerous tissues. Additionally, overexpression of NONHSAT105177 inhibited PDAC cell proliferation, migration, and the epithelial-mesenchymal transition (EMT), both in vitro and in vivo. Consistent with the mechanism of action of melittin, NONHSAT105177 significantly downregulated cholesterol pathway genes, including Clusterin (CLU). Moreover, we found that NONHSAT105177 trafficking was mediated by exosomes. The combined findings of our current and previous studies suggest that NONHSAT105177 mediated the melittin-induced inhibition of PDAC cell growth and metastasis, which indicated a potential target for developing new strategies.

Topics: Adenocarcinoma; Animals; Cell Line; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Exosomes; Gene Expression Regulation, Neoplastic; Humans; Male; Melitten; Mice; Mice, Nude; Microarray Analysis; Pancreatic Neoplasms; RNA, Long Noncoding; Wound Healing

Melittin is a Chinese traditional medicine for treating chronic inflammation, immunological diseases and cancers, however, the efficacy of melittin and its mechanism for treating pancreatic ductal adenocarcinoma (PDAC) are still unknown. Here we investigated the anti-cancer activity of melittin and its regulated mechanism(s) in the PDAC models. Melittin was found to suppress tumor growth by promoting cell apoptosis and cell-cycle arrest. Interestingly, the microarray analyses demonstrated that melittin significantly regulated cholesterol biosynthesis pathway during treatment. For instance, the cholesterol pathway gene clusterin (CLU) was highly downregulated by melittin which also enhanced gemcitabine sensitivity in PDAC cells by inhibiting CLU expression. In contrast, overexpression of CLU significantly diminished melittin mediated tumor suppression and gemcitabine sensitization, suggesting that CLU is the target of melittin. Furthermore, in the xenograft mouse model, the combination therapy of melittin and gemcitabine is more efficacious for inhibiting PDAC tumor growth than either single regimen. Taken together, our study has indicated that melittin is capable of suppressing tumor growth and promoting gemcitabine sensitivity in PDAC by downregulating cholesterol pathway.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Proliferation; Cholesterol; Clusterin; Deoxycytidine; Dose-Response Relationship, Drug; Down-Regulation; Drug Resistance, Neoplasm; Gemcitabine; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Male; Melitten; Mice, Nude; Pancreatic Neoplasms; Protein Kinase Inhibitors; Signal Transduction; Time Factors; Transfection; Tumor Burden; Xenograft Model Antitumor Assays