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Functional characterization of CLPTM1L as a lung cancer risk candidate gene in the 5p15.33 locus. PLoS One 2012;7(6):e36116 PMID: 22675468 PMCID: PMC3366984

Pubmed ID

22675468

DOI

10.1371/journal.pone.0036116

Abstract

Cleft Lip and Palate Transmembrane Protein 1-Like (CLPTM1L), resides in a region of chromosome 5 for which copy number gain has been found to be the most frequent genetic event in the early stages of non-small cell lung cancer (NSCLC). This locus has been found by multiple genome wide association studies to be associated with lung cancer in both smokers and non-smokers. CLPTM1L has been identified as an overexpressed protein in human ovarian tumor cell lines that are resistant to cisplatin, which is the only insight thus far into the function of CLPTM1L. Here we find CLPTM1L expression to be increased in lung adenocarcinomas compared to matched normal lung tissues and in lung tumor cell lines by mechanisms not exclusive to copy number gain. Upon loss of CLPTM1L accumulation in lung tumor cells, cisplatin and camptothecin induced apoptosis were increased in direct proportion to the level of CLPTM1L knockdown. Bcl-xL accumulation was significantly decreased upon loss of CLPTM1L. Expression of exogenous Bcl-xL abolished sensitization to apoptotic killing with CLPTM1L knockdown. These results demonstrate that CLPTM1L, an overexpressed protein in lung tumor cells, protects from genotoxic stress induced apoptosis through regulation of Bcl-xL. Thus, this study implicates anti-apoptotic CLPTM1L function as a potential mechanism of susceptibility to lung tumorigenesis and resistance to chemotherapy.

Author List

James MA, Wen W, Wang Y, Byers LA, Heymach JV, Coombes KR, Girard L, Minna J, You M

Authors

Michael James PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Yian Wang MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-84861899749   63 Citations

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Apoptosis
Cell Line, Tumor
Chromosomes, Human, Pair 5
DNA Damage
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Genetic Association Studies
Genetic Loci
Genetic Predisposition to Disease
Humans
Lung Neoplasms
Membrane Proteins
Mutagens
Neoplasm Proteins
Risk Factors
bcl-X Protein
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e