P70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression in orthotopic mouse non-muscle invasive bladder tumor model.
We investigated how the dual inhibition of the molecular mechanism of the mammalian target of the rapamycin (mTOR) downstreams, P70S6 kinase (P70S6K) and eukaryotic initiation factor 4E (eIF4E), can lead to a suppression of the proliferation and progression of urothelial carcinoma (UC) in an orthotopic mouse non-muscle invasive bladder tumor (NMIBT) model. A KU-7-luc cell intravesically instilled orthotopic mouse NMIBC model was monitored using bioluminescence imaging (BLI) in vivo by interfering with different molecular components using rapamycin and siRNA technology. We then analyzed the effects on molecular activation status, cell growth, proliferation, and progression. A high concentration of rapamycin (10 µM) blocked both P70S6K and elF4E phosphorylation and inhibited cell proliferation in the KU-7-luc cells. It also reduced cell viability and proliferation more than the transfection of siRNA against p70S6K or elF4E. The groups with dual p70S6K and elF4E siRNA, and rapamycin reduced tumor volume and lamina propria invasion more than the groups with p70S6K or elF4E siRNA instillation, although all groups reduced photon density compared to the control. These findings suggest that both the mTOR pathway downstream of eIF4E and p70S6K can be successfully inhibited by high dose rapamycin only, and p70S6K and Elf4E dual inhibition is essential to control bladder tumor growth and progression.
Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea.
Byung Hoon
0000-0002-4184-7780
BH
Chi
Biomedical Science, Department of Medicine, Chung-Ang University Graduate School, Seoul, Korea.
Soon-Ja
0000-0003-2359-4422
SJ
Kim
Center for Prostate Cancer, Research Institute, National Cancer Center, Goyang, Korea.
Ho Kyung
0000-0003-2601-1093
HK
Seo
Genitourinary Cancer Branch, Research Institute, National Cancer Center, Goyang, Korea.
Hye-Hyun
0000-0003-4070-9367
HH
Seo
Genitourinary Cancer Branch, Research Institute, National Cancer Center, Goyang, Korea.
Sang-Jin
0000-0002-4478-1043
SJ
Lee
Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea.
Jong Kyou
0000-0002-6143-7586
JK
Kwon
Department of Pathology, Chung-Ang University College of Medicine, Seoul, Korea.
Tae-Jin
0000-0003-2539-3579
TJ
Lee
Department of Urology, Chung-Ang University College of Medicine, Seoul, Korea.
In Ho
0000-0003-0240-1310
IH
Chang
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors* / Q000235:genetics; D005260:Female; D051379:Mice; D008819:Mice, Nude; D009092:Mucous Membrane / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology*; D019459:Urothelium / Q000473:pathology
D039561:Eukaryotic Initiation Factor-4E; D034741:RNA, Small Interfering; C000601282:eIF4E protein, mouse; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Mouse Orthotopic Model; Urinary Bladder Neoplasms; mTOR