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Down-regulation of Sprouty2 in non-small cell lung cancer contributes to tumor malignancy via extracellular signal-regulated kinase pathway-dependent and -independent mechanisms

Lookup NU author(s): Professor Johannes Attems


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Sprouty (Spry) proteins function as inhibitors of receptor tyrosine kinase signaling mainly by interfering with the Ras/Raf/mitogen-activated protein kinase cascade, a pathway known to be frequently deregulated in human non-small cell lung cancer (NSCLC). In this study, we show a consistently lowered Spry2 expression in NSCLC when compared with the corresponding normal lung epithelium. Based on these findings, we investigated the influence of Spry2 expression on the malignant phenotype of NSCLC cells. Ectopic expression of Spry2 antagonized mitogen-activated protein kinase activity and inhibited cell migration in cell lines homozygous for K-Ras wild type, whereas in NSCLC cells expressing mutated K-Ras, Spry2 failed to diminish extracellular signal-regulated kinase (ERK) phosphorylation. Nonetheless, Spry2 significantly reduced cell proliferation in all investigated cell lines and blocked tumor formation in mice. Accordingly, a Spry2 mutant unable to inhibit ERK phosphorylation reduced cell proliferation significantly but less pronounced compared with the wild-type protein. Therefore, we conclude that Spry2 interferes with ERK phosphorylation and another yet unidentified pathway. Our results suggest that Spry2 plays a role as tumor suppressor in NSCLC by antagonizing receptor tyrosine kinase-induced signaling at different levels, indicating feasibility for the usage of Spry in targeted gene therapy of NSCLC.

Publication metadata

Author(s): Sutterluty H, Mayer CE, Setinek U, Attems J, Ovtcharov S, Mikula M, Mikulits W, Micksche M, Berger W

Publication type: Article

Publication status: Published

Journal: Molecular Cancer Research

Year: 2007

Volume: 5

Issue: 5

Pages: 509-520

ISSN (print): 1541-7786

ISSN (electronic): 1557-3125

Publisher: American Association for Cancer Research


DOI: 10.1158/1541-7786.MCR-06-0273

Notes: Sutterluty, Hedwig Mayer, Christoph-Erik Setinek, Ulrike Attems, Johannes Ovtcharov, Slav Mikula, Mario Mikulits, Wolfgang Micksche, Michael Berger, Walter Research Support, Non-U.S. Gov't United States Molecular cancer research : MCR Mol Cancer Res. 2007 May;5(5):509-20.


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