linical Development pression of Neurotensin Receptor Type 1 Expression and ction by Histone Deacetylase Inhibitors in Human Ther orectal Cancers

Downlo rotensin, a gut peptide, stimulates the growth of colorectal cancers that possess the high-affinity neuin receptor (NTR1). Sodium butyrate (NaBT) is a potent histone deacetylase inhibitor (HDACi) that s growth arrest, differentiation, and apoptosis of colorectal cancers. Previously, we had shown that increases nuclear GSK-3β expression and kinase activity; GSK-3β functions as a negative regulator acellular signal-regulated kinase (ERK) signaling. The purpose of our current study was to determine: ether HDACi alters NTR1 expression and function, and (b) the role of GSK-3β/ERK in NTR1 regulauman colorectal cancers with NTR1 were treated with various HDACi, and NTR1 expression and n were assessed. Treatment with HDACi dramatically decreased endogenous NTR1 mRNA, protein, romoter activity. Overexpression of GSK-3β decreased NTR1 promoter activity (> 30%); inhibition of β increased NTR1 expression in colorectal cancer cells, indicating that GSK-3β is a negative regulator of nd NTR1. Consistent with our previous findings, HDACi significantly decreased phosphorylated ERK increasingGSK-3β. SelectiveMAP/ERK kinase/ERK inhibitors suppressedNTR1mRNAexpression in a nd dose-dependent fashion, and reduced NTR1 promoter activity by ∼70%. Finally, pretreatment with prevented neurotensin-mediated cyclooxygenase-2 and c-myc expression and attenuated neurotensind interleukin-8 expression. HDACi suppresses endogenous NTR1 expression and function in colorectal cell lines; this effect is mediated, at least in part, through the GSK-3β/ERK pathway. The downregulacancer tion of NTR1 in colorectal cancers may represent an important mechanism for the anticancer effects of HDACi. Mol Cancer Ther; 9(8); 2389–98. ©2010 AACR.