Activated mTOR/P70S6K signaling pathway is involved in insulinoma tumorigenesis.
BACKGROUND
Insulinoma was a rare tumor and its pathogenesis was poorly understood. There had no study that focused on the role of mTOR signaling pathway in insulinoma tumorigenesis.


METHODS
Expression of p-mTOR and its downstream p-P70S6K in insulinoma and normal pancreatic tissue was evaluated by immunohistochemical staining and Western blotting. In vitro study, an insulinoma cell line (INS-1) was treated with inhibitors of mTOR (rapamycin) or dual PI3K/mTOR inhibitor (NVP-BEZ235), RT-PCR, and Western blotting were applied to evaluate their influence on the expression of mTOR and P70S6K. Cell proliferation was evaluated by MTT test, cell cycle and apoptosis were analyzed by flow cytometry, insulin secretion level was evaluated by GSIS method.


RESULTS
Positive expression of p-mTOR and p-P70S6K was much higher in insulinoma tumor specimens than the normal pancreatic islet (P < 0.05). mTOR inhibitors can induce decreased expression of mTOR and P70S6K, which resulting in inhibiting INS-1 cell proliferation, insulin secretion and inducing apoptosis. NVP-BEZ235 had better influence on inhibiting the cell proliferation and inducing apoptosis than rapamycin.


CONCLUSIONS
mTOR/P70S6K signaling pathway is involved in tumorigenesis of insulinoma, NVP-BEZ235 and rapamycin offer a promising role as novel drugs in treatment of insulinoma.
Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, P.R. China.
Han-Xiang
HX
Zhan
Lin
L
Cong
Yu-Pei
YP
Zhao
Tai-Ping
TP
Zhang
Ge
G
Chen
Li
L
Zhou
Jun-Chao
JC
Guo
D000328:Adult; D005260:Female; D006801:Humans; D007340:Insulinoma / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases