Abstract 2196: Tumor suppressor LKB1 cooperates with the integrin-binding protein Nischarin to inhibit breast cancer

Abstract

Abstract Tumor metastasis still remains the main cause of breast cancer death. Although with chemotherapy and radiation therapy, the prognosis has improved in some cases, these approaches often result in severe side effects. It is therefore imperative to elucidate the molecular targets which can prevent metastasis. Two tumor suppressor proteins, Nischarin and LKB1, have been implicated in suppressing metastasis. A novel protein, Nischarin has an inhibitory role in cancer cell migration and invasion; it affects the process of cytoskeletal regulation mediated by Rac and PAK [1]. Nischarin binds to PAK1 and inhibits the kinase activity of PAK1. Nischarin also suppresses breast tumor growth and metastasis in vivo (unpublished results). LKB1 is a serine/threonine kinase involved in the progression of Peutz-Jegher syndrome (PJS) and is also known to play a role in the suppression of breast cancer [2]. Since Nischarin has structural similarities with LKB1 interacting protein (LIP1)[3], we hypothesized that Nischarin interacts with LKB1. Using co-immunoprecipitation assays we have shown that Nischarin interacts with LKB1 in breast cancer cell lines. Our confocal microscopy data confirm that endogenous Nischarin and LKB1 co-localize in the cytosol. Furthermore, we demonstrate that the amino-terminus of Nischarin binds to the kinase domain of LKB1. Nischarin is expressed primarily in the cytoplasm whereas LKB1 is predominantly nuclear with only a small portion of it being in the cytosol, and the cytoplasmic fraction of LKB1 is important for its tumor suppressor function. Our preliminary biochemical fractionation data indicate that Nischarin expression leads to cytoplasmic relocalization of LKB1 suggesting that Nischarin may regulate LKB1 function by regulating its sub cellular localization. Moreover, our random cell migration data using time-lapse microcopy indicate that cancer cell displacement and speed is greatly reduced when both Nischarin and LKB1 are expressed. Hence, it appears that LKB1 cooperates with Nischarin to inhibit breast cancer tumor growth and metastasis. Thus, the studies will be important in determining the role of the LKB-Nischarin interaction in breast cancer, and will likely provide a foundation for subsequent preclinical and clinical studies. This work was supported by the grant from NIH 5RO1CA115706. 1. Alahari, S.K., Nischarin inhibits Rac induced migration and invasion of epithelial cells by affecting signaling cascades involving PAK. Exp Cell Res, 2003. 288(2): p. 415-24. 2. Zhuang, Z.G., et al., Enhanced expression of LKB1 in breast cancer cells attenuates angiogenesis, invasion, and metastatic potential. Mol Cancer Res, 2006. 4(11): p. 843-9. 3. Smith, D.P., et al., LIP1, a cytoplasmic protein functionally linked to the Peutz-Jeghers syndrome kinase LKB1. Hum Mol Genet, 2001. 10(25): p. 2869-77. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2196. doi:10.1158/1538-7445.AM2011-2196