Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix: A potential biomarker and molecular target therapy.
Alterations of the Akt/mTOR pathway have been observed in numerous types of cancer, thus this pathway represents an exciting new target for molecular therapeutics. We investigated the expression of activated Akt (p-Akt) and mTOR (p-mTOR) in patients with adenocarcinoma of the cervix and the involvement of the p-Akt/p-mTOR pathway in response to combination of inhibitor agents, rapamycin and LY294002, with conventional therapy, cisplatin, in vitro. Immunohistochemistry analysis of p-Akt and p-mTOR was conducted in 26 patients with adenocarcinoma of the cervix. Western blot analysis was performed to determine the protein expression involved in response to chemotherapy in cervical cancer cell lines. The results showed that p-Akt and p-mTOR were identified in 50% and 53.8% of adenocarcinoma of the cervix. The expression of p-mTOR was a significant independent marker for prognosis. A significant correlation between p-Akt and p-mTOR was observed. There was no correlation between their expressions with any of clinicopathological factors. In the in vitro study, cisplatin at CPI(50) targets both the apoptosis and survival pathway by activating the caspase-cascade; inhibiting Akt, mTOR, p70S6K, and 4EBP1. Combination of rapamycin with cisplatin induced synergistic interaction. On the other hand, combination with LY294002 resulted in either synergistic or antagonistic effect depending on the doses given. Rapamycin pretreatment potentiated cisplatin-induced apoptosis cell death and enhanced blocking of the survival pathway. Overall, the expression of p-mTOR is a significant prognostic marker of adenocarcinoma of the cervix and a potential molecular target for the treatment of cervical cancer. Inhibition of the mTOR pathway contributes to cisplatin-induced apoptosis in cervical cancer cell lines.
Department of Gynecology and Reproductive Medicine, Graduate School of Medicine, Gunma University, Gunma, Japan.
Leri S
LS
Faried
Ahmad
A
Faried
Tatsuya
T
Kanuma
Hiroshi
H
Aoki
Takaaki
T
Sano
Tomoko
T
Nakazato
Tomohiro
T
Tamura
Hiroyuki
H
Kuwano
Takashi
T
Minegishi
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D011379:Prognosis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases