Dataset Information

Decitabine reverses gefitinib resistance in PC9 lung adenocarcinoma cells by demethylation of RASSF1A and GADD45? promoter.

ABSTRACT: The acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the major reason for the failure of target therapy in advanced non small cell lung cancer (NSCLC) patients, the mechanism of which has not been fully elucidated yet. The present study aimed to investigate the different DNA methylation profile before and after acquired EGFR-TKI resistance, and explore the influence of the DNA demethylater, decitabine, on EGFR-TKI resistance. The DNA methylation chip was used to screen the genes whose DNA methylation status were changed in the EGFR-TKI sensitive human NSCLC cell line PC9, and the induced EGFR-TKI resistant NSCLC cell line PC9/GR (harboring T790M mutation). According to the results and literature reports, the tumor suppressor genes, RASSF1A and GADD45? were selected for further research. Methylation specific PCR (MSP) and western blot further confirmed that the promoters of these two genes were methylated, and the protein expressions were significantly inhibited in PC9/GR cells. Additionally, decitabine, the DNA methyl transferase inhibitor, could reverse the methylation status of RASSF1A and GADD45? promoters, elevate protein expression, and partially restore the sensitivity of PC9/GR cells to EGFR-TKI. To conclude, our results suggested that the DNA methylation of RASSF1 and GADD45? may play a role in EGFR-TKI resistance, and epigenetic intervention might be an effective strategy to reverse EGFR-TKI resistance, suggesting further study.

SUBMITTER: Hou T

PROVIDER: S-EPMC6949799 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Decitabine reverses gefitinib resistance in PC9 lung adenocarcinoma cells by demethylation of RASSF1A and GADD45β promoter.

Hou Tao T Ma Jin'an J Hu Chunhong C Zou Fangwen F Jiang Shun S Wang Yapeng Y Han Chen C Zhang Ying Y

International journal of clinical and experimental pathology 20191101 11

The acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the major reason for the failure of target therapy in advanced non small cell lung cancer (NSCLC) patients, the mechanism of which has not been fully elucidated yet. The present study aimed to investigate the different DNA methylation profile before and after acquired EGFR-TKI resistance, and explore the influence of the DNA demethylater, decitabine, on EGFR-TKI resistance. The DNA methylation chi ...[more]

PMID: 31933796

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Project description:Non-small cell lung cancer is a subtype of adenocarcinoma, which has previously shown positive responses to gefitinib. The aim of the current study was to determine a clinical profile of gefitinib-induced disease controls for patients with lung adenocarcinoma. Retrospective evaluation of the clinical characteristics of 52 lung adenocarcinoma patients, enrolled at the Zhejiang Cancer Hospital (Hangzhou, China) between October 2004 and August 2008, was undertaken. All patients received gefitinib (250 mg/day orally) until disease progression or until an unacceptable toxicity was observed. Of the 52 patients, complete response (CR) and partial response (PR) rates were 23.1% (12/52) and 57.7% (30/52), respectively. An additional 19.2% (10/52) of patients demonstrated stable disease (SD) after three months of treatment with gefitinib. Disease control was observed in the primary lesion, and tumor metastasis to the lungs, brain, adrenal glands, pleura, peritoneum, pericardium, bone and lymph nodes was identified. The one-year progression-free survival (PFS) and overall survival (OS) rates were 74.8 and 78.0%, respectively. Multivariate analysis revealed that female patients were associated with significantly longer survival times when compared with males (hazard ratio, 0.077; 95% confidence interval [CI], 0.007-0.083; P=0.035). One-year PFS and OS rates in CR, PR and SD patients were 77.8, 73.9 and 33.3%, and 89.2, 79.8 and 33.7%, respectively, although neither difference was identified to be statistically significant. In addition, the median OS of SD patients was 12 months (95% CI, 7.2-16.8 months). Brain metastasis was the major site of disease progression (23.1%). Gefitinib treatment for patients with lung adenocarcinoma showed a marked long-term survival benefit, even in SD patients. However, further studies are required to analyze the efficacy of gefitinib in penetrating the blood-brain barrier in order to prolong PFS in patients with lung adenocarcinoma.

Project description:BackgroundOur previous studies have identified CA916798 as a chemotherapy resistance-associated gene in lung cancer. However, the histopathological relevance and biological function of CA916798 in lung adenocarcinoma (LUAD) remains to be delineated. In this study, we further investigated and explored the clinical and biological significance of CA916798 in LUAD.MethodsThe relationship between CA916798 and clinical features of LUAD was analyzed by tissue array and online database. CCK8 and flow cytometry were used to measure cell proliferation and cell cycle of LUAD after knockdown of CA916798 gene. qRT-PCR and western blotting were used to detect the changes of cell cycle-related genes after knockdown or overexpression of CA916798. The tumorigenesis of LUAD cells was evaluated with or without engineering manipulation of CA916798 gene expression. Response to Gefitinib was evaluated using LUAD cells with forced expression or knockdown of CA916798.ResultsThe analysis on LUAD samples showed that high expression of CA916798 was tightly correlated with pathological progression and poor prognosis of LUAD patients. A critical methylation site in promoter region of CA916798 gene was identified to be related with CA916798 gene expression. Forced expression of CA916798 relieved the inhibitory effects of WEE1 on CDK1 and facilitated cell cycle progression from G2 phase to M phase. However, knockdown of CA916798 enhanced WEE1 function and resulted in G2/M phase arrest. Consistently, chemical suppression of CDK1 dramatically inhibited G2/M phase transition in LUAD cells with high expression of CA916798. Finally, we found that CA916798 was highly expressed in Gefitinib-resistant LUAD cells. Exogenous expression of CA916798 was sufficient to endow Gefitinib resistance with tumor cells, but interference of CA916798 expression largely rescued response of tumor cells to Gefitinib.ConclusionsCA916798 played oncogenic roles and was correlated with the development of Gefitinib resistance in LUAD cells. Therefore, CA916798 could be considered as a promising prognostic marker and a therapeutic target for LUAD.

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Decitabine reverses gefitinib resistance in PC9 lung adenocarcinoma cells by demethylation of RASSF1A and GADD45? promoter.

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Decitabine reverses gefitinib resistance in PC9 lung adenocarcinoma cells by demethylation of RASSF1A and GADD45β promoter.

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