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Regulation of PTEN Expression in Intestinal Epithelial Cells by c-Jun NH₂-Terminal Kinase Activation and Nuclear Factor-B Inhibition

¹ Department of Surgery and ² the Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas

Requests for reprints: B. Mark Evers, Department of Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0536. Phone: 409-772-5254; Fax: 409-747-4819; E-mail: mevers{at}utmb.edu.

The tumor suppressor protein phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in intestinal cell proliferation and differentiation and tumor suppression by antagonizing phosphatidylinositol 3-kinase. Despite its importance, the molecular mechanisms regulating PTEN expression are largely undefined. Here, we show that treatment of the colon cancer cell line HT29 with the differentiating agent sodium butyrate (NaBT) increased PTEN protein and mRNA expression and induced c-Jun NH₂-terminal kinase (JNK) activation. Inhibition of JNK by chemical or genetic methods attenuated NaBT-induced PTEN expression. In addition, our findings showed a cross-talk between nuclear factor B (NF-B) and JNK with respect to PTEN regulation. Overexpression of the NF-B superrepressor increased PTEN expression and JNK activity, whereas overexpression of the p65 NF-B subunit reduced both basal and NaBT-mediated JNK activation and PTEN expression. Moreover, we showed that overexpression of PTEN or treatment with NaBT increased expression of the cyclin-dependent kinase inhibitor p27^kip1 in HT29 cells; this induction was attenuated by inhibition of PTEN or JNK expression or overexpression of p65. Finally, we show a role for PTEN in NaBT-mediated cell death and differentiation. Our findings suggest that the JNK/PTEN and NF-B/PTEN pathways play a critical role in normal intestinal homeostasis and colon carcinogenesis. [Cancer Res 2007;67(16):7773–81]