ArticleCell death & disease2015
Reciprocal positive regulation between Cx26 and PI3K/Akt pathway confers acquired gefitinib resistance in NSCLC cells via GJIC-independent induction of EMT.
Article in Cell death & disease, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 75 citations in OpenAlex.
- GJB2, a novel transcription target of HSF4, confers tumorigenic and metastatic phenotypes and sustains mitochondrial homeostasis in lung adenocarcinoma via the PI3K/AKT pathway.Cell adhesion & migration · 2026Article
- Single-cell RNA profiling reveals an immunosuppressive microenvironment inTranslational lung cancer research · 2025Article
- CX26 promotes pancreatic cancer progression by competitively inhibiting interaction of c-Myc with PSMD2 and enhancing c-Myc stability.Journal of translational medicine · 2025Article
- GJB2 as a novel prognostic biomarker associated with immune infiltration and cuproptosis in ovarian cancer.Apoptosis : an international journal on programmed cell death · 2025Article
- Article
- Aidi injection inhibits the migration and invasion of gefitinib-resistant lung adenocarcinoma cells by regulating the PLAT/FAK/AKT pathway.Chinese medicine · 2025Article
- Coordination of innate immune responses by connexins.Frontiers in immunology · 2025Review
- Interplay between lncRNAs and the PI3K/AKT signaling pathway in the progression of digestive system neoplasms (Review).International journal of molecular medicine · 2025Review
- Chemoresistance and the tumor microenvironment: the critical role of cell-cell communication.Cell communication and signaling : CCS · 2024Review
- GJB2 Promotes HCC Progression by Activating Glycolysis Through Cytoplasmic Translocation and Generating a Suppressive Tumor Microenvironment Based on Single Cell RNA Sequencing.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Integrative analyses identified gap junction beta-2 as a prognostic biomarker and therapeutic target for breast cancer.Cancer innovation · 2024Article
- Metformin suppresses NFE2L1 pathway activation to inhibit gap junction beta protein expression in NSCLC.Cancer medicine · 2024Article
- Cell Death, by Any Other Name….Cells · 2024Review
- The clinical significance of endoplasmic reticulum stress related genes in non-small cell lung cancer and analysis of single nucleotide polymorphism for CAV1.Frontiers in molecular biosciences · 2024Article
- Multi-omics analysis of expression profile and prognostic values of connexin family in LUAD.Journal of cancer research and clinical oncology · 2023Article
- Connexins in Cancer, the Possible Role of Connexin46 as a Cancer Stem Cell-Determining Protein.Biomolecules · 2023Review
- [Methylselenocysteine Promotes Etoposide Cytotoxicity by Enhancing Homotypic Gap Junctions Composed of Connexin 26].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2023Article
- The roles of connexins and gap junctions in the progression of cancer.Cell communication and signaling : CCS · 2023Review
- Pan-cancer analysis of the prognostic and immunological role of GJB2: a potential target for survival and immunotherapy.Frontiers in oncology · 2023Review
- Cytoplasmic localization of connexin 26 suppresses transition of β-catenin into the nucleus in intestinal- and mix-type gastric cancer.Annals of gastroenterological surgery · 2022Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.