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Bile Acid Exposure Up-regulates Tuberous Sclerosis Complex 1/Mammalian Target of Rapamycin Pathway in Barrett's-Associated Esophageal Adenocarcinoma

Departments of ¹ Molecular and Cellular Oncology, ² Experimental Therapeutics, ³ Gastrointestinal Medicine and Nutrition, ⁴ Gastrointestinal Medical Oncology, ⁵ Pathology, and ⁶ Molecular Pathology, University of Texas M. D. Anderson Cancer Center; ⁷ Graduate School of Biomedical Sciences, University of Texas, Houston, Texas; ⁸ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; ⁹ Institute of Clinical Medicine, Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan; and ¹⁰ Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University Hospital, Taichung, Taiwan

Requests for reprints: Mien-Chie Hung, Department of Molecular and Cellular Oncology, Unit 108, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3668; Fax: 713-794-3270; E-mail: mhung{at}mdanderson.org.

Key Words: bile acid • IKKβ/TSC1/mTOR • Barrett's associated esophageal adenocarcinoma

Barrett's esophagus, a columnar metaplasia of the lower esophagus epithelium related to gastroesophageal reflux disease, is the strongest known risk factor for the development of esophageal adenocarcinoma (EAC). Understanding the signal transduction events involved in esophageal epithelium carcinogenesis may provide insights into the origins of EAC and may suggest new therapies. To elucidate the molecular pathways of bile acid–induced tumorigenesis, the newly identified inflammation-associated signaling pathway involving IB kinases β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1) was confirmed to be activated in immortalized Barrett's CPC-A and CPC-C cells and esophageal cancer SEG-1 and BE3 cells. Phosphorylation of TSC1 and S6K1 was induced in response to bile acid stimulation. Treatment of these cells with the mTOR inhibitor rapamycin or the IKKβ inhibitor Bay 11-7082 suppressed bile acid–induced cell proliferation and anchorage-independent growth. We next used an orthotopic rat model to evaluate the role of bile acid in the progression of Barrett's esophagus to EAC. Of interest, we found high expression of phosphorylated IKKβ (pIKKβ) and phosphorylated S6K1 (pS6K1) in tumor tissues and the Barrett's epithelium compared with normal epithelium. Furthermore, immunostaining of clinical EAC tissue specimens revealed that pIKKβ expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKKβ signaling, which may play a critical role in EAC progression. In addition, Bay 11-7082 and rapamycin may potentially be chemopreventive drugs against Barrett's esophagus–associated EAC. [Cancer Res 2008;68(8):2632–40]