Document Detail


PTEN inactivation in lung cancer cells and the effect of its recovery on treatment with epidermal growth factor receptor tyrosine kinase inhibitors.
MedLine Citation:
PMID:  17912443     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
To understand the mechanisms of PTEN inactivation, which is reported to be involved in tumor progression and drug resistance in lung cancer, we analyzed the expression levels of PTEN at mRNA and protein levels, along with the genetic and epigenetic status of the PTEN gene, in a panel of lung cancer cell lines. Western blot analysis showed that six out of 25 (24%) cell lines displayed low expression of PTEN protein. The level of PTEN mRNA correlated well with corresponding protein expression in each of these six cell lines. In two of the six cell lines genomic analysis revealed homozygous deletions of the PTEN gene. Another two of the six cell lines displayed hypermethylation of the PTEN gene promoter assessed by methylation-specific PCR. The levels of PTEN mRNA and protein expression in PC9/f9 and PC9/f14 cells, which are gefitinib-resistant derivatives of the gefitinib-sensitive cell line, PC9, were reduced compared to the parental line. After treatment with the demethylating agent 5-aza-2'deoxycytidine (5-AZA) and the histone deacetyltransferase (HDAC) inhibitor Trichostatin A (TSA), the expression levels of PTEN mRNA and protein in these four cell lines (PC9/f9, PC9/f14, PC10 and PC14) were actually restored. In summary, reduction in PTEN protein expression was regulated by histone deacetylation and hypermethylation of the gene promoter, as well as homozygous deletion. In addition, we demonstrated that the combination treatment of gefitinib and TSA induced significant growth inhibition in gefitinib-resistant PC9/f9 and PC9/f14 cells. These findings suggest that the combination of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib with the demethylating agent 5-AZA and the HDAC inhibitor TSA may be a useful strategy for the treatment of some lung cancers.
Authors:
Rintaro Noro; Akihiko Gemma; Akihiko Miyanaga; Seiji Kosaihira; Yuji Minegishi; Michiya Nara; Yutaka Kokubo; Masahiro Seike; Kiyoko Kataoka; Kuniko Matsuda; Tetsuya Okano; Akinobu Yoshimura; Shoji Kudoh
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of oncology     Volume:  31     ISSN:  1019-6439     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2007 Nov 
Date Detail:
Created Date:  2007-10-03     Completed Date:  2007-12-20     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1157-63     Citation Subset:  IM    
Affiliation:
Department of Pulmonary Medicine/Infection and Oncology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
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MeSH Terms
Descriptor/Qualifier:
Cell Line, Tumor
DNA Methylation
Humans
Hydroxamic Acids / pharmacology
Lung Neoplasms / drug therapy*,  genetics,  pathology
PTEN Phosphohydrolase / genetics*
Polymerase Chain Reaction
Protein Kinase Inhibitors / pharmacology*
Quinazolines / pharmacology*
Receptor, Epidermal Growth Factor / antagonists & inhibitors*
Sequence Analysis, DNA
Chemical
Reg. No./Substance:
0/Hydroxamic Acids; 0/Protein Kinase Inhibitors; 0/Quinazolines; 3X2S926L3Z/trichostatin A; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase; S65743JHBS/gefitinib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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