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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.
Mol Cancer Res. 2007 May; 5(5):509-20.MC

Abstract

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.

Authors+Show Affiliations

Institute of Cancer Research, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria. hedwig.sutterluety@meduniwien.ac.atNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17510316

Citation

Sutterlüty, Hedwig, et al. "Down-regulation of Sprouty2 in Non-small Cell Lung Cancer Contributes to Tumor Malignancy Via Extracellular Signal-regulated Kinase Pathway-dependent and -independent Mechanisms." Molecular Cancer Research : MCR, vol. 5, no. 5, 2007, pp. 509-20.
Sutterlüty H, Mayer CE, Setinek U, et al. Down-regulation of Sprouty2 in non-small cell lung cancer contributes to tumor malignancy via extracellular signal-regulated kinase pathway-dependent and -independent mechanisms. Mol Cancer Res. 2007;5(5):509-20.
Sutterlüty, H., Mayer, C. E., Setinek, U., Attems, J., Ovtcharov, S., Mikula, M., Mikulits, W., Micksche, M., & Berger, W. (2007). Down-regulation of Sprouty2 in non-small cell lung cancer contributes to tumor malignancy via extracellular signal-regulated kinase pathway-dependent and -independent mechanisms. Molecular Cancer Research : MCR, 5(5), 509-20.
Sutterlüty H, et al. Down-regulation of Sprouty2 in Non-small Cell Lung Cancer Contributes to Tumor Malignancy Via Extracellular Signal-regulated Kinase Pathway-dependent and -independent Mechanisms. Mol Cancer Res. 2007;5(5):509-20. PubMed PMID: 17510316.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Down-regulation of Sprouty2 in non-small cell lung cancer contributes to tumor malignancy via extracellular signal-regulated kinase pathway-dependent and -independent mechanisms. AU - Sutterlüty,Hedwig, AU - Mayer,Christoph-Erik, AU - Setinek,Ulrike, AU - Attems,Johannes, AU - Ovtcharov,Slav, AU - Mikula,Mario, AU - Mikulits,Wolfgang, AU - Micksche,Michael, AU - Berger,Walter, PY - 2007/5/19/pubmed PY - 2007/6/30/medline PY - 2007/5/19/entrez SP - 509 EP - 20 JF - Molecular cancer research : MCR JO - Mol. Cancer Res. VL - 5 IS - 5 N2 - 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. SN - 1541-7786 UR - https://www.unboundmedicine.com/medline/citation/17510316/Down_regulation_of_Sprouty2_in_non_small_cell_lung_cancer_contributes_to_tumor_malignancy_via_extracellular_signal_regulated_kinase_pathway_dependent_and__independent_mechanisms_ L2 - http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17510316 DB - PRIME DP - Unbound Medicine ER -