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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

Date

12/25/2013

Pubmed ID

24366883

Pubmed Central ID

PMC6005686

DOI

10.1158/0008-5472.CAN-13-1617

Scopus ID

2-s2.0-84894226710 (requires institutional sign-in at Scopus site)   57 Citations

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

Author

Amy Rymaszewski PhD Research Scientist I in the Pediatrics department at Medical College of Wisconsin




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