Rapamycin inhibits cell proliferation in type I and type II endometrial carcinomas: a search for biomarkers of sensitivity to treatment.
OBJECTIVE
Our goal was to evaluate the effect of rapamycin, an mTOR inhibitor, in type I and II human endometrial cancer tumor explants.


METHODS
Short-term tissue culture with fresh endometrial cancer tumor explants was performed. Cell proliferation was assessed by MTS assay after treatment with rapamycin. Akt and PTEN status were documented by Western blotting. The effect of rapamycin on phosphorylated-S6 and 4E-BP-1 was also assessed by Western blotting. Real-time RT-PCR was used to quantify hTERT mRNA expression. Telomere length was determined by terminal restriction fragment Southern blotting.


RESULTS
Thirteen fresh endometrial cancer tumor explants (nine Type I, four Type II) were placed in short-term culture and treated with rapamycin. Nine of the endometrial cancer tumors responded to rapamycin, with a median IC₅₀ of 11.4 nM. Sensitivity to rapamycin was independent of PTEN and Akt status. Tumors (13/13) had a reduction in phosphorylated-S6 and 10/13 had a reduction in phosphorylated 4E-BP-1. Rapamycin decreased hTERT mRNA expression in all of the endometrial cancer tumors. Telomere length did not correspond with responsiveness to this drug.


CONCLUSIONS
Rapamycin demonstrated activity in fresh endometrial tumor explants independent of PTEN and Akt status. Some tumors demonstrated a reduction in phosphorylated-S6 and 4E-BP-1 without a significant change in cellular proliferation, suggesting that additional pathways may modulate cellular proliferation. Thus, mTOR inhibitors may be a useful targeted therapy for both type I and type II endometrial cancers, but the search remains for a predictive biomarker of sensitivity to this therapy.
Bae-Jump
Victoria L
VL
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Zhou
Chunxiao
C
Boggess
John F
JF
Whang
Young E
YE
Barroilhet
Lisa
L
Gehrig
Paola A
PA
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C509186:TERT protein, human; D019098:Telomerase; D020123:Sirolimus