Relationship between long non-coding RNA PCAT-1 expression and gefitinib resistance in non-small-cell lung cancer
Shaojia Wang1, Chao Liu2, Qing Lei3
1Department of Gynecology, The Third Affiliated Hospital of Kunming Medical University, Yunnan Cancer Hospital, Yunnan Cancer Center, Kunming, 650118, China.
Background:
Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been used as first-line treatment for advanced non-small-cell lung cancer (NSCLC). However, during treatment, cancer cells often develop resistance to gefitinib, the mechanisms of which are not fully understood. This study was designed to elucidate the expression and role of long non-coding RNA (lncRNA)-PCAT-1, a potential biomarker for drug resistance and a therapeutic target for NSCLC, in gefitinib resistance in NSCLC cells.
Methods:
In this study, we verified differential PCAT-1 expression in NSCLC gefitinib-resistant tissues or cells. PCAT-1 knockdown, clone formation, Transwell, flow cytometry, and immunofluorescence assays were used to verify the correlation between PCAT-1 and gefitinib sensitivity. A nude mouse tumor-bearing model verified that PCAT-1 can reverse gefitinib resistance in vivo. Then, a PI3K/Akt agonist was used to verify the possible mechanism of PCAT-1 action.
Results:
PCAT-1 is highly expressed in gefitinib-resistant NSCLC tissues and cells. PCAT-1 knockdown enhanced gefitinib sensitivity and gefitinib-induced apoptosis in H1299/GR cells. PCAT-1 knockdown reduced tumor volume and weight, and reversed acquired gefitinib resistance in vivo. PCAT-1 knockdown inhibited AKT and GSK3 phosphorylation in H1299/GR cells. A PI3K/AKT agonist reversed PCAT-1 knockdown-mediated enhancement of gefitinib sensitivity in H1299/GR cells CONCLUSION: PCAT-1 knockdown improves sensitivity to gefitinib by inhibition of AKT and GSK3 phosphorylation in NSCLC. PCAT-1 is as potential target for improving the clinical efficacy of gefitinib.
Insights
Long non-coding RNA PCAT-1 promotes gefitinib resistance in non-small-cell lung cancer (NSCLC) by activating the PI3K/Akt pathway. Inhibiting PCAT-1 can restore sensitivity to gefitinib, offering a potential therapeutic strategy for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Gefitinib is a first-line treatment for advanced non-small-cell lung cancer (NSCLC).
- Acquired resistance to gefitinib is a significant clinical challenge in NSCLC treatment.
- The precise mechanisms underlying gefitinib resistance remain incompletely understood.
Purpose of the Study:
- To investigate the role of long non-coding RNA (lncRNA)-PCAT-1 in gefitinib resistance in NSCLC.
- To explore PCAT-1 as a potential biomarker and therapeutic target for overcoming gefitinib resistance.
Main Methods:
- Differential expression analysis of PCAT-1 in gefitinib-resistant NSCLC tissues and cells.
- Functional assays including PCAT-1 knockdown, clone formation, Transwell, flow cytometry, and immunofluorescence.
- In vivo studies using a nude mouse tumor-bearing model.
- Mechanism investigation using a PI3K/Akt agonist.
Main Results:
- PCAT-1 was significantly upregulated in gefitinib-resistant NSCLC.
- PCAT-1 knockdown enhanced gefitinib sensitivity and apoptosis in resistant cells.
- In vivo, PCAT-1 knockdown reduced tumor growth and reversed gefitinib resistance.
- PCAT-1 knockdown inhibited AKT and GSK3 phosphorylation, a pathway reversed by a PI3K/AKT agonist.
Conclusions:
- PCAT-1 knockdown resensitizes NSCLC cells to gefitinib by inhibiting AKT and GSK3 phosphorylation.
- PCAT-1 represents a promising therapeutic target for improving gefitinib efficacy in NSCLC.
More Related Videos
09:38Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
13:34A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
