Relationship between long non-coding RNA PCAT-1 expression and gefitinib resistance in non-small-cell lung cancer cells

Abstract

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.

Non-coding RNAs as potential therapeutic targets for receptor tyrosine kinase signaling in solid tumors: current status and future directions

“…Thereby, lncRNA H19 seems to be a key factor in regulating RTK signaling [ 178 ]. RTKIs with a similar effect on the mentioned pathways on UCA1 [ 179 ], CRNDE [ 180 ], and PCAT1 [ 181 ] genes lead to the development of other types of NSCLCs. In an alternative mechanism, LncRNA-SARCC functions as a suppressor of the androgen receptor (AR) protein, hindering the propagation of its downstream signals involving AKT, MMP-13, K-RAS, and P-ERK.…”

Receptor tyrosine kinase inhibitors in cancer

“…Wang et al also reported that knockdown of long non-coding RNA (lncRNA)-PCAT-1, an important factor in resistance to ge tinib in NSCLC cells, could improved the sensitivity to ge tinib, increase apoptosis, and inhibit GSK3 and AKT phosphorylation in H1299/GR cells. Thus this lncRNA could be a potential target for enhancing ge tinib e cacy (110). In another study by Satoh et al, combination therapy with erlotinib, bevacizumab plus osimertinib after acquired resistance emerged in NSCLC patients could be an option for these patients suffering from acquired resistance therapy to osimertinib alone (111).…”

Long non-coding RNA and Evolving drug resistance in lung cancer

“…Sun et al reported that lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) promoted the NSCLC tumorigenesis and gefitinib resistance of NSCLC by repressing the EphB3 via recruiting LSD1 [ 123 ]. Wang et al showed that PCAT-1 was highly expressed in gefitinib-resistant NSCLC tissues and cells, and PCAT-1 knockdown sensitized NSCLC to gefitinib by inhibiting AKT and GSK3 phosphorylation in NSCLC [ 124 ]. PCAT6 has been found to confer to gefitinib resistance of NSCLC via miR-326/IFNAR2 axis [ 125 ].…”