title: CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis.
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.
authors.affiliation: Authors' Affiliation: MCW Cancer Center, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Michael A
authors.initials: MA
authors.lastname: James
authors.forename: Haris G
authors.initials: HG
authors.lastname: Vikis
authors.forename: Everett
authors.initials: E
authors.lastname: Tate
authors.forename: Amy L
authors.initials: AL
authors.lastname: Rymaszewski
authors.forename: Ming
authors.initials: M
authors.lastname: You
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D011905:Genes, ras / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C422445:CLPTM1L protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins