Regulation of TRAIL expression by the phosphatidylinositol 3-kinase/Akt/GSK-3 pathway in human colon cancer cells

Qingding Wang, Xiaofu Wang, Ambrosio Hernandez, Mark Hellmich, Zoran Gatalica, B. Mark Evers

Research output: Contribution to journalArticle

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Abstract

The intestinal mucosa is a rapidly-renewing tissue characterized by cell proliferation, differentiation, and eventual apoptosis with progression up the vertical gut axis. The inhibition of phosphatidylinositol (PI) 3-kinase by specific chemical inhibitors or overexpression of the lipid phosphatase PTEN enhances enterocyte-like differentiation in human colon cancer cell models of intestinal differentiation. In this report, we examined the role of PI 3-kinase inhibition in the regulation of apoptotic gene expression in human colon cancer cell lines HT29, HCT-116, and Caco-2. Inhibition of PI 3-kinase with the chemical inhibitor wortmannin increased TNF-related apoptosis-inducing ligand (TRAIL; Apo2) mRNA and protein expression. Similarly, overexpression of the tumor suppressor protein PTEN, an antagonist of PI 3-kinase signaling, resulted in the increased expression of TRAIL. Activation of PI 3-kinase by pre-treatment with IGF-1, a gut trophic factor, markedly attenuated the induction of TRAIL by wortmannin. Moreover, overexpression of active Akt, a downstream target of PI 3-kinase, or inhibition of GSK-3, a down-stream target of active Akt, completely blocked the induction of TRAIL by wortmannin. Consistent with findings that TRAIL is induced by agents that enhance intestinal cell differentiation, TRAIL expression was specifically localized to the differentiated cells of the colon and small bowel. Adenovirus-mediated overexpression of TRAIL increased DNA fragmentation of HCT-116 cells, demonstrating the functional activity of TRAIL induction. Taken together, our findings demonstrate induction of the TRAIL by inhibition of PI 3-kinase in colon cancer cell lines. These results identify TRAIL, a novel TNF family member, as a downstream target of the PI 3-kinase/Akt/GSK-3 pathway and may have important implications for better understanding the role of the PI 3-kinase pathway in intestinal cell homeostasis.

Original languageEnglish (US)
Pages (from-to)36602-36610
Number of pages9
JournalJournal of Biological Chemistry
Volume277
Issue number39
DOIs
StatePublished - Sep 27 2002

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Phosphatidylinositol 3-Kinase
Glycogen Synthase Kinase 3
Colonic Neoplasms
Cells
proctolin
Cell Differentiation
PTEN Phosphohydrolase
TNF-Related Apoptosis-Inducing Ligand
HCT116 Cells
Tumor Suppressor Proteins
Cell Line
Enterocytes
Cell proliferation
Gene Expression Regulation
DNA Fragmentation
Intestinal Mucosa
Insulin-Like Growth Factor I
Adenoviridae
Gene expression
Colon

ASJC Scopus subject areas

  • Biochemistry

Cite this

Regulation of TRAIL expression by the phosphatidylinositol 3-kinase/Akt/GSK-3 pathway in human colon cancer cells. / Wang, Qingding; Wang, Xiaofu; Hernandez, Ambrosio; Hellmich, Mark; Gatalica, Zoran; Mark Evers, B.

In: Journal of Biological Chemistry, Vol. 277, No. 39, 27.09.2002, p. 36602-36610.

Research output: Contribution to journalArticle

Wang, Qingding ; Wang, Xiaofu ; Hernandez, Ambrosio ; Hellmich, Mark ; Gatalica, Zoran ; Mark Evers, B. / Regulation of TRAIL expression by the phosphatidylinositol 3-kinase/Akt/GSK-3 pathway in human colon cancer cells. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 39. pp. 36602-36610.
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