TY - JOUR
T1 - Mammalian Target of Rapamycin (mTOR) regulates cellular proliferation and tumor growth in urothelial carcinoma
AU - Hansel, Donna E.
AU - Platt, Eric
AU - Orloff, Mohammed
AU - Harwalker, Jyoti
AU - Sethu, Swathi
AU - Hicks, Jessica L.
AU - De Marzo, Angelo
AU - Steinle, Roxanne E.
AU - Hsi, Eric D.
AU - Theodorescu, Dan
AU - Ching, Christina B.
AU - Eng, Charis
N1 - Funding Information:
Supported in part by a pilot program grant from the Cleveland Clinical and Translational Sciences Collaborative (CTSC) of Case Western Reserve University (to D.E.H.), the American Cancer Society Ohio Pilot Research grant (to D.E.H.), a KL2 Career Development Award (to D.E.H.), and the M. Frank and Margaret Domiter Rudy Chair fund. C.E. is a recipient of the Doris Duke Distinguished Clinical Scientist Award, is an ACS Clinical Research Professor, and is the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic.
PY - 2010/6
Y1 - 2010/6
N2 - Mammalian target of rapamycin (mTOR) signaling has been associated with aggressive tumor growth in many cancer models, although its role in urothelial carcinoma (UCC) has not been extensively explored. Expression of phosphorylated mTOR (P-mTOR) and a downstream target, ribosomal S6 protein (P-S6), was identified in 74% (90/121) and 55% (66/121) of muscle-invasive UCCs, respectively. P-mTOR intensity and %positive cells were associated with reduced disease-specific survival (P = 0.04, P = 0.08, respectively). Moreover, P-mTOR intensity corresponded to increased pathological stage (P < 0.01), and mTOR activity was associated with cell migration in vitro. In addition, mTOR inhibition via rapamycin administration reduced cell proliferation in UCC cell lines RT4, T24, J82, and UMUC3 in a dose-dependent manner to 6% of control levels and was significant at 1 nmol/L in J82, T24, and RT4 cells (P < 0.01, P < 0.01, P = 0.03, respectively) and at 10 nmol/L in UMUC3 cells (P = 0.03). Reduced proliferation corresponded with reduced P-S6 levels by Western blot, and effects were ablated by pretreatment of cells with mTOR-specific siRNA. No effects of rapamycin on apoptosis were identified by TUNEL labeling or PARP cleavage. Administration of rapamycin to T24-xenografted mice resulted in a 55% reduction in tumor volume (P = 0.03) and a 40% reduction in proliferation (P < 0.01) compared with vehicle-injected mice. These findings indicate that mTOR pathway activation frequently occurs in UCC and that mTOR inhibition may be a potential means to reduce UCC growth.
AB - Mammalian target of rapamycin (mTOR) signaling has been associated with aggressive tumor growth in many cancer models, although its role in urothelial carcinoma (UCC) has not been extensively explored. Expression of phosphorylated mTOR (P-mTOR) and a downstream target, ribosomal S6 protein (P-S6), was identified in 74% (90/121) and 55% (66/121) of muscle-invasive UCCs, respectively. P-mTOR intensity and %positive cells were associated with reduced disease-specific survival (P = 0.04, P = 0.08, respectively). Moreover, P-mTOR intensity corresponded to increased pathological stage (P < 0.01), and mTOR activity was associated with cell migration in vitro. In addition, mTOR inhibition via rapamycin administration reduced cell proliferation in UCC cell lines RT4, T24, J82, and UMUC3 in a dose-dependent manner to 6% of control levels and was significant at 1 nmol/L in J82, T24, and RT4 cells (P < 0.01, P < 0.01, P = 0.03, respectively) and at 10 nmol/L in UMUC3 cells (P = 0.03). Reduced proliferation corresponded with reduced P-S6 levels by Western blot, and effects were ablated by pretreatment of cells with mTOR-specific siRNA. No effects of rapamycin on apoptosis were identified by TUNEL labeling or PARP cleavage. Administration of rapamycin to T24-xenografted mice resulted in a 55% reduction in tumor volume (P = 0.03) and a 40% reduction in proliferation (P < 0.01) compared with vehicle-injected mice. These findings indicate that mTOR pathway activation frequently occurs in UCC and that mTOR inhibition may be a potential means to reduce UCC growth.
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U2 - 10.2353/ajpath.2010.090872
DO - 10.2353/ajpath.2010.090872
M3 - Article
C2 - 20395440
AN - SCOPUS:77953180987
SN - 0002-9440
VL - 176
SP - 3062
EP - 3072
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -