Editors' ChoiceCancer

TPL2, a MAPKKK That Suppresses Lung Cancer

Science Signaling  23 Apr 2013:
Vol. 6, Issue 272, pp. ec93
DOI: 10.1126/scisignal.2004262

Tumor progression locus 2 (TPL2), also known as COT (cancer Osaka thyroid) and MAP3K8 (mitogen-activated kinase kinase kinase 8), is a kinase involved in the inflammatory immune response, but reports on its roles in cancer development are conflicting. Gkirtzimanaki et al. found that TPL2 may be a tumor suppressor in lung tissue. TPL2 expression was decreased in a large sample of human lung carcinomas, and low expression correlated with increased proliferative index and decreased patient survival. Compared with wild-type mice, TPL2–/– mice exposed to the carcinogen urethane showed increased proliferation of hyperplastic lesions, earlier development of adenocarcinomas, increased bronchiolar invasion, and decreased expression of p53 target genes bax and cdkn1a. Lung tumors isolated from wild-type mice showed decreased expression of TPL2 compared with normal bronchial epithelium. No differences in immune cell infiltration and inflammatory cytokine secretion were observed in lungs or spleens of TPL2–/– and wild-type mice, indicating an immune- and inflammation-independent oncogenic response to TPL2 deletion. In human lung cancer tissue with a low amount of TPL2, Gkirtzimanaki et al. found loss of heterozygosity of TPL2, activating mutations of Ras, or increased abundance of microRNA (miR)–370, the locus of which was hypomethylated. Transfection with miR-370 (but not miR-328) or mutant H-Ras or K-Ras decreased TPL2 abundance in A549 and H1299 lung cancer cells, suggesting potential causes of TPL2 loss in lung cancer. Transfection of H-Ras mutant A549 cells or K-Ras mutant 208F fibroblasts with TPL2 reduced cell proliferation and increased apoptosis, effects that were impaired by treatment with pan-caspase inhibitors or p53-targeted siRNA. In cisplatin-treated cells, TPL2 knockdown decreased both the phosphorylation of JNK (c-Jun N-terminal kinase) and the abundance of nucleophosmin (NPM), which has binding sites for c-Jun in its promoter and stabilizes p53 by inhibiting its interaction with the ubiquitin ligase MDM2. Overexpression of TPL2 in H-Ras mutant A549 cells increased JNK phosphorylation and NPM and p53 abundance, all of which were diminished by pretreatment with a JNK inhibitor. The findings suggest that TPL2 promotes p53-mediated tumor suppression in lung cells through a JNK-NPM pathway.

K. Gkirtzimanaki, K. K. Gkouskou, U. Oleksiewicz, G. Nikolaidis, D. Vyrla, M. Liontos, V. Pelekanou, D. C. Kanellis, K. Evangelou, E. N. Stathopoulos, J. K. Field, P. N. Tsichlis, V. Gorgoulis, T. Liloglou, A. G. Eliopoulos, TPL2 kinase is a suppressor of lung carcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 110, E1470–E1479 (2013). [Abstract] [Full Text]