title: Oridonin inhibits gefitinib-resistant lung cancer cells by suppressing EGFR/ERK/MMP-12 and CIP2A/Akt signaling pathways.
abstract: Oridonin (Ori), a diterpenoid compound extracted from traditional medicinal herbs, elicits antitumor effects on many cancer types. However, whether Ori can be used in gefitinib-resistant non-small cell lung cancer (NSCLC) cells remains unclear. This study investigated the antitumor activity and underlying mechanisms of Ori. Results demonstrated that this compound dose-dependently inhibited the proliferation, invasion, and migration of the gefitinib-resistant NSCLC cells in vitro. Ori also significantly downregulated the phosphorylation of EGFR, ERK, Akt, expression levels of matrix metalloproteinase-12 (MMP-12), and the cancerous inhibitor of protein phosphatase 2A (CIP2A). In addition, Ori upregulated protein phosphatase 2A (PP2A) activity of gefitinib-resistant NSCLC cells. Ori combined with docetaxel synergistically inhibited these cells. Ori also inhibited tumor growth in murine models. Immunohistochemistry results further revealed that Ori downregulated phospho-EGFR, MMP-12, and CIP2A in vivo. These findings indicated that Ori can inhibit the proliferation, invasion, and migration of gefitinib-resistant NSCLC cells by suppressing EGFR/ERK/MMP-12 and CIP2A/PP2A/Akt signaling pathways. Thus, Ori may be a novel effective candidate to treat gefitinib-resistant NSCLC.
authors.affiliation: School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Xiangling
authors.initials: X
authors.lastname: Xiao
authors.affiliation: School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: He
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.affiliation: School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Fen
authors.initials: F
authors.lastname: Cai
authors.affiliation: School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Qiuyue
authors.initials: Q
authors.lastname: Huang
authors.affiliation: School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Fan
authors.affiliation: School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Duan
authors.affiliation: Translational Medical Center, Suizhou Central Hospital, Hubei University of Medicine, Suizhou, Hubei 441300, P.R. China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Jiu
authors.initials: J
authors.lastname: Wang
authors.affiliation: School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000072283:A549 Cells; D000818:Animals; D001324:Autoantigens / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D001324:Autoantigens; C500266:CIP2A protein, human; D045786:Diterpenes, Kaurane; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011799:Quinazolines; C011959:oridonin; C512478:EGFR protein, human; D066246:ErbB Receptors; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D000077156:Gefitinib