1. CRR9/CLPTM1L Regulates Cell Survival Signaling and Is Required for Ras Transformation and Lung Tumorigenesis.
- Author
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James, Michael A., Vikis, Haris G., Tate, Everett, Rymaszewski, Amy L., and Ming You
- Subjects
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NON-small-cell lung carcinoma , *MEMBRANE proteins , *CANCER cells , *APOPTOSIS , *PROTEIN kinases , *LUNG cancer treatment - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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