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Lung cancer cell migration is regulated via repressing growth factor PTN/RPTP ?/? signaling by menin.

ABSTRACT: Menin encoded by the multiple endocrine neoplasia type 1 (MEN1) gene is associated with chromatin and the nuclear matrix and exerts multiple biological functions including regulation of cell proliferation and adhesion. Men1 mutations increase the likelihood of lung cancer development in mice. Menin expression is reduced in certain human non-small cell lung cancer cells, and reduction of menin is closely correlated with increased lung cancer metastasis to lymph nodes. However, it is poorly understood whether menin affects migration of lung cancer cells. In this study, we show that menin-regulated A549 lung cancer cell migration, which was mediated by growth factor pleiotrophin (PTN) and its cell surface receptor, protein tyrosine phosphatase beta/zeta (RPTP ?/?). Ectopic menin expression significantly repressed PTN transcription, but indirectly inhibited RPTP ?/? expression through repressing PTN expression. Further studies revealed that menin-regulated cell migration through PTN/RPTP ?/?, in conjunction with integrin ?(v)?(3), focal adhesion kinase, phosphatidylinositol 3-kinase and phosphorylated extracellular signal regulated kinase 1/2. These findings provide mechanistic insights into the molecular basis for menin/PTN-mediated regulation of A549 lung cancer cell migration.

SUBMITTER: Feng ZJ

PROVIDER: S-EPMC3007126 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Lung cancer cell migration is regulated via repressing growth factor PTN/RPTP β/ζ signaling by menin.

Feng Z-J ZJ Gao S-B SB Wu Y Y Xu X-F XF Hua X X Jin G-H GH

Oncogene 20100719 39

Menin encoded by the multiple endocrine neoplasia type 1 (MEN1) gene is associated with chromatin and the nuclear matrix and exerts multiple biological functions including regulation of cell proliferation and adhesion. Men1 mutations increase the likelihood of lung cancer development in mice. Menin expression is reduced in certain human non-small cell lung cancer cells, and reduction of menin is closely correlated with increased lung cancer metastasis to lymph nodes. However, it is poorly unders ...[more]

PMID: 20639902

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Project description:Lung cancer is the second most common cancer and the leading cause of cancer-related deaths. Despite recent advances in the development of targeted therapies, patients with advanced disease remain incurable, mostly because metastatic non-small cell lung carcinomas (NSCLC) eventually become resistant to tyrosine kinase inhibitors (TKIs). Kinase inhibitors have the potential for target promiscuity because the kinase super family is the largest family of druggable genes that binds to a common substrate (ATP). As a result, TKIs often developed for a specific purpose have been found to act on other targets. Drug affinity chromatography has been used to show that dasatinib interacts with the TGF? type I receptor (T?R-I), a serine-threonine kinase. To determine the potential biological relevance of this association, we studied the combined effects of dasatinib and TGF? on lung cancer cell lines. We found that dasatinib treatment alone had very little effect; however, when NSCLC cell lines were treated with a combination of TGF? and dasatinib, apoptosis was induced. Combined TGF?-1 + dasatinib treatment had no effect on the activity of Smad2 or other non-canonical TGF? intracellular mediators. Interestingly, combined TGF? and dasatinib treatment resulted in a transient increase in p-Smad3 (seen after 3 hours). In addition, when NSCLC cells were treated with this combination, the pro-apoptotic protein BIM was up-regulated. Knockdown of the expression of Smad3 using Smad3 siRNA also resulted in a decrease in BIM protein, suggesting that TGF?-1 + dasatinib-induced apoptosis is mediated by Smad3 regulation of BIM. Dasatinib is only effective in killing EGFR mutant cells, which is shown in only 10% of NSCLCs. Therefore, the observation that wild-type EGFR lung cancers can be manipulated to render them sensitive to killing by dasatinib could have important implications for devising innovative and potentially more efficacious treatment strategies for this disease.

Dataset Information

Lung cancer cell migration is regulated via repressing growth factor PTN/RPTP ?/? signaling by menin.

Publications

Lung cancer cell migration is regulated via repressing growth factor PTN/RPTP β/ζ signaling by menin.

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