title: Reciprocal positive regulation between Cx26 and PI3K/Akt pathway confers acquired gefitinib resistance in NSCLC cells via GJIC-independent induction of EMT.
abstract: Gefitinib efficiency in non-small-cell lung cancer (NSCLC) therapy is limited due to development of drug resistance. The molecular mechanisms of gefitinib resistance remain still unclear. In this study, we first found that connexin 26 (Cx26) is the predominant Cx isoform expressed in various NSCLC cell lines. Then, two gefitinib-resistant (GR) NSCLC cell lines, HCC827 GR and PC9 GR, from their parental cells were established. In these GR cells, the results showed that gefitinib resistance correlated with changes in cellular EMT phenotypes and upregulation of Cx26. Cx26 was detected to be accumulated in the cytoplasm and failed to establish functional gap-junctional intercellular communication (GJIC) either in GR cells or their parental cells. Ectopic expression of GJIC-deficient chimeric Cx26 was sufficient to induce EMT and gefitinib insensitivity in HCC827 and PC9 cells, while knockdown of Cx26 reversed EMT and gefitinib resistance in their GR cells both in vitro and in vivo. Furthermore, Cx26 overexpression could activate PI3K/Akt signaling in these cells. Cx26-mediated EMT and gefitinib resistance were significantly blocked by inhibition of PI3K/Akt pathway. Specifically, inhibition of the constitutive activation of PI3K/Akt pathway substantially suppressed Cx26 expression, and Cx26 was confirmed to functionally interplay with PI3K/Akt signaling to promote EMT and gefitinib resistance in NSCLC cells. In conclusion, the reciprocal positive regulation between Cx26 and PI3K/Akt signaling contributes to acquired gefitinib resistance in NSCLC cells by promoting EMT via a GJIC-independent manner.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, China.
authors.forename: G
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Pharmacology, School of Pharmacy, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, China.
authors.forename: M
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Cancer Hospital, Guangxi Medical University, 71 Hedi Road, Nanning 530021, Guangxi, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmacy, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary, Department of Medicine, Allergy and Critical Care, Lung Biology Laboratory, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Nephrology Division, The First Affiliated Hospital, Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi, China.
authors.forename: L
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Respiratory Medicine, The First Affiliated Hospital, Guangxi Medical University, 6 Shuangyong Road, Nanning 530021, Guangxi, China.
authors.forename: S
authors.initials: S
authors.lastname: Qin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D017629:Gap Junctions; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D000072259:Connexin 26; D017630:Connexins; D000077156:Gefitinib; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one