| First Author | James MA | Year | 2014 |
| Journal | Cancer Res | Volume | 74 |
| Issue | 4 | Pages | 1116-27 |
| PubMed ID | 24366883 | Mgi Jnum | J:208170 |
| Mgi Id | MGI:5561192 | Doi | 10.1158/0008-5472.CAN-13-1617 |
| Citation | James MA, et al. (2014) CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis. Cancer Res 74(4):1116-27 |
| abstractText | 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. |
