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CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis. Cancer Res 2014 Feb 15;74(4):1116-27 PMID: 24366883 PMCID: PMC6005686

Pubmed ID

24366883

DOI

10.1158/0008-5472.CAN-13-1617

Abstract

The transmembrane protein CLPTM1L is overexpressed in non-small cell lung cancer, where it protects tumor cells from genotoxic apoptosis. Here, we show that RNA interference-mediated blockade of CLPTM1L inhibits K-Ras-induced lung tumorigenesis. CLPTM1L expression was required in vitro for morphologic transformation by H-RasV12 or K-RasV12, anchorage-independent growth, and survival of anoikis of lung tumor cells. Mechanistic investigations indicated that CLPTM1L interacts with phosphoinositide 3-kinase and is essential for Ras-induced AKT phosphorylation. Furthermore that the anti-apoptotic protein Bcl-xL is regulated by CLPTM1L independently of AKT activation. Constitutive activation of AKT or Bcl-xL rescued the transformed phenotype in CLPTM1L-depleted cells. The CLPTM1L gene lies within a cancer susceptibility locus at chromosome 5p15.33 defined by genome-wide association studies. The risk genotype at the CLPTM1L locus was associated with high expression of CLPTM1L in normal lung tissue, suggesting that cis-regulation of CLPTM1L may contribute to lung cancer risk. Taken together, our results establish a protumorigenic role for CLPTM1L that is critical for Ras-driven lung cancers, with potential implications for therapy and chemosensitization.

Author List

James MA, Vikis HG, Tate E, Rymaszewski AL, You M

Authors

Michael James PhD Assistant Professor in the Surgery 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-s2.0-84894226710   31 Citations

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

Animals
Carcinoma, Non-Small-Cell Lung
Cell Survival
Cell Transformation, Neoplastic
Genes, ras
HEK293 Cells
Humans
Lung Neoplasms
Membrane Proteins
Mice
Mice, Nude
NIH 3T3 Cells
Neoplasm Proteins
Signal Transduction
Tumor Cells, Cultured
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e