title: PI3K inhibitor combined with miR-125b inhibitor sensitize TMZ-induced anti-glioma stem cancer effects through inactivation of Wnt/β-catenin signaling pathway.
abstract: Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly with a high frequency. Glioblastoma stem cells (GSCs) causing resistance to drug therapy were considered to be one of the key factors. The mechanisms underlying GSCs resistance to TMZ are not fully understood. MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance. Our previous studies showed that miR-125b was necessary for GSCs fission, and inhibition of which could enhance the chemosensitivity of GSCs to TMZ. Recent studies have evidence that a variety of drugs and upstream factors work through PI3K/Akt pathway, and the effects of PI3K/Akt pathway inhibition on GSCs were much more than non-GSCs. In this study, we found that PI3K inhibitor combined with miR-125b inhibitor caused a marked increase of TMZ-induced GSC proliferation and invasiveness inhibition. To explore the potential mechanism, we found that this novel combinatorial regimen leads to changes of inactivation of Wnt/β-catenin pathway which regulates a series of cell activities including cell apoptosis, proliferation, differentiation, and metabolism. Taken together, our data strongly support an important role for PI3K inhibitor and miR-125b inhibitor on conferring GSCs resistance to TMZ through targeting Wnt/β-catenin signaling pathway.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China. sl1012002322@126.com.|Department of Neurosurgery, The First People's Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, 215300, People's Republic of China. sl1012002322@126.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Department of Neurosurgery, School of Medicine, Suzhou Kowloon Hospital Affiliated with Shanghai Jiao Tong University, Suzhou, 215021, People's Republic of China.
authors.forename: Xifeng
authors.initials: X
authors.lastname: Fei
authors.affiliation: Department of Neurosurgery, School of Medicine, Suzhou Kowloon Hospital Affiliated with Shanghai Jiao Tong University, Suzhou, 215021, People's Republic of China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China. yypl9@njmu.edu.cn.
authors.forename: Yongping
authors.initials: Y
authors.lastname: You
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061251:Primary Cell Culture; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002867:Chromones; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051153:Wnt Proteins; D051176:beta Catenin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003606:Dacarbazine; D000077204:Temozolomide
keywords: Glioblastoma; MiR-125b; Stem cells; Temozolomide