Bile acid exposure up-regulates tuberous sclerosis complex 1/mammalian target of rapamycin pathway in 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 I kappaB kinases beta (IKK beta), 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 IKK beta 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 IKK beta (pIKK beta) 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 pIKK beta expression was strongly correlated with pS6K1 level. Together, these results show that bile acid can deregulate TSC1/mTOR through IKK beta 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.
Yen
Chia-Jui
CJ
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Izzo
Julie G
JG
Lee
Dung-Fang
DF
Guha
Sushovan
S
Wei
Yongkun
Y
Wu
Tsung-Teh
TT
Chen
Chun-Te
CT
Kuo
Hsu-Ping
HP
Hsu
Jung-Mao
JM
Sun
Hui-Lung
HL
Chou
Chao-Kai
CK
Buttar
Navtej S
NS
Wang
Kenneth K
KK
Huang
Peng
P
Ajani
Jaffer
J
Hung
Mien-Chie
MC
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D001471:Barrett Esophagus / Q000150:complications* / Q000503:physiopathology; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002455:Cell Division; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D005764:Gastroesophageal Reflux / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000503:physiopathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D001647:Bile Acids and Salts; D016328:NF-kappa B; D009570:Nitriles; D034741:RNA, Small Interfering; D013450:Sulfones; C000624650:TSC1 protein, human; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus