The mTOR pathway affects proliferation and chemosensitivity of urothelial carcinoma cells and is upregulated in a subset of human bladder cancers.
OBJECTIVE
To investigate whether mammalian target of rapamycin (mTOR) inhibition by rapamycin is therapeutically efficacious in combination with cisplatin for bladder cancer.


METHODS
Using a panel of human urothelial carcinoma cell lines, we determined the effect of rapamycin on cell viability, cell-cycle progression, signalling and apoptosis. The effect of mTOR inhibition on chemosensitivity was investigated by treating cells with rapamycin, alone, or with cisplatin. The effect of rapamycin or cisplatin treatment was assessed in xenograft mice inoculated with urothelial carcinoma cells. Expression of p-mTOR in human bladder cancer specimens was assessed using a tissue microarray.


RESULTS
Treatment with rapamycin significantly decreased cell viability in UMUC3 (P = 0.004) and 253J (P < 0.001) cells. It induced arrest in the G(0) -G(1) phase and decreased activation of p-mTOR and its downstream effector, p-S6K, in both cell lines. Treatment with rapamycin increased the ability of cisplatin to inhibit cell viability in UMUC3 (P = 0.002) and 253J (P = 0.03) cells. No evidence for apoptosis induction was noted after treatment with rapamycin alone. Mouse xenografts of UMUC3 cells revealed that rapamycin significantly prolonged survival and enhanced the therapeutic efficacy of cisplatin. In patient urothelial carcinoma specimens, p-mTOR expression was increased in cancer vs non-tumour bladder tissue in 65/203 (32.0%) tumours.


CONCLUSIONS
mTOR blockade inhibits urothelial carcinoma cell proliferation and enhances the effectiveness of cisplatin. Suppression of the mTOR pathway has the potential to be a therapeutic target in bladder cancer for selected patients.
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
Igor
I
Makhlin
Jiaru
J
Zhang
Christopher J
CJ
Long
Karthik
K
Devarajan
Yan
Y
Zhou
Andres J
AJ
Klein-Szanto
Min
M
Huang
Jonathan
J
Chernoff
Stephen A
SA
Boorjian
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002295:Carcinoma, Transitional Cell / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019459:Urothelium / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus