期刊
CANCER RESEARCH
卷 67, 期 16, 页码 7773-7781出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-0187
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- NCI NIH HHS [R01 CA104748-03, R01 CA104748] Funding Source: Medline
- NIA NIH HHS [R37 AG010885, R37 AG010885-15, R37 AG10885] Funding Source: Medline
- NIDDK NIH HHS [P01 DK035608, R01 DK048498-11, P01 DK035608-200001, R01 DK048498, R01 DK48498, P01 DK35608] Funding Source: Medline
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 kB (NF-kB) and JNK with respect to PTEN regulation. Overexpression of the NF-kB superrepressor increased PTEN expression and JNK activity, whereas overexpression of the p65 NF-kB 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-kB/PTEN pathways play a critical role in normal intestinal homeostasis and colon carcinogenesis.
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