Rapamycin inhibits telomerase activity by decreasing the hTERT mRNA level in endometrial cancer cells.
Rapamycin exerts its biological activity by inhibiting the kinase mammalian target of rapamycin (mTOR), which regulates important cellular processes such as control of cell cycle and cell size, translation initiation, and transcription. The ability of rapamycin to inhibit cancer cell proliferation has led to efforts to develop rapamycin and related mTOR inhibitors as anticancer agents. Some investigators have hypothesized that loss of the PTEN tumor suppressor may sensitize tumor cells to the antiproliferative activity of rapamycin because PTEN loss leads to activation of the mTOR pathway. Because PTEN loss is frequent in endometrial cancer, we have characterized the effect of rapamycin in endometrial cancer cells. We show that rapamycin in the nanomolar concentration range exerts a potent growth-inhibitory effect on endometrial cancer cells through induction of cell cycle arrest. This effect is independent of PTEN status because PTEN-positive ECC-1 cells are as sensitive to rapamycin as PTEN-null Ishikawa and Hec-1B cells, suggesting that rapamycin may be effective against a broad range of endometrial cancers. We also show that rapamycin rapidly inhibits telomerase activity by decreasing the mRNA level of hTERT, the catalytic subunit of telomerase. This implies that rapamycin leads to inhibition of hTERT gene transcription. We demonstrate that rapamycin inhibits phosphorylation of downstream targets of mTOR such as p70(S6K) kinase and 4E-BP1 translation repressor. This work suggests that rapamycin is a potentially useful targeted therapy for endometrial cancer and that loss of telomerase activity may be a good surrogate biomarker for assessing antitumor activity of rapamycin.
Zhou
Chunxiao
C
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Gehrig
Paola A
PA
Whang
Young E
YE
Boggess
John F
JF
D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D005260:Female; D006801:Humans; D011494:Protein Kinases / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D019098:Telomerase; D020123:Sirolimus