title: Targeting miR-21 sensitizes Ph+ ALL Sup-b15 cells to imatinib-induced apoptosis through upregulation of PTEN.
abstract: Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) cells are insensitive to BCR-ABL tyrosine kinase inhibitor imatinib, the underlying mechanisms remain largely unknown. Here, we showed that imatinib treatment induced significant upregulation of miR-21 and downregulation of PTEN in Ph+ ALL cell line Sup-b15. Transient inhibition of miR-21 resulted in increased apoptosis, PTEN upregulation and AKT dephosphorylation, whereas ectopic overexpression of miR-21 further conferred imatinib resistance. Furthermore, knockdown of PTEN protected the cells from imatinib-induced apoptosis achieved by inhibition of miR-21. Additionally, PI3K inhibitors also notably enhanced the effects of imatinib on Sup-b15 cells and primary Ph+ ALL cells similar to miR-21 inhibitor. Therefore, miR-21 contributes to imatinib resistance in Ph+ ALL cells and antagonizing miR-21 demonstrates therapeutic potential by sensitizing the malignancy to imatinib therapy.
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China; Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Wei-Zhang
authors.initials: WZ
authors.lastname: Wang
authors.affiliation: Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Xiang-Hua
authors.initials: XH
authors.lastname: Lin
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Qiao-Hong
authors.initials: QH
authors.lastname: Pu
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Man-Yu
authors.initials: MY
authors.lastname: Liu
authors.affiliation: Department of Hematology, Guangzhou General Hospital of Guangzhou Military Area Command of Chinese PLA, Guangzhou, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Wu
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China; Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Wu
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Jian-Wen
authors.initials: JW
authors.lastname: Mao
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Jia-Yong
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China. Electronic address: jinxf2001@163.com.
authors.forename: Xiao-Bao
authors.initials: XB
authors.lastname: Jin
mesh_terms: D000070416:Antagomirs; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D009841:Oligonucleotides / Q000494:pharmacology*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000070416:Antagomirs; D000970:Antineoplastic Agents; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C520440:antagomir-122; D000068877:Imatinib Mesylate; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Apoptosis; Imatinib; MiR-21; PTEN; Sup-b15 cells