A critical role for choline kinase-alpha in the aggressiveness of bladder carcinomas.
Bladder cancer is one of the most common causes of death in industrialized countries. New tumor markers and therapeutic approaches are still needed to improve the management of bladder cancer patients. Choline kinase-alpha (ChoKalpha) is a metabolic enzyme that has a role in cell proliferation and transformation. Inhibitors of ChoKalpha show antitumoral activity and are expected to be introduced soon in clinical trials. This study aims to assess whether ChoKalpha plays a role in the aggressiveness of bladder tumors and constitutes a new approach for bladder cancer treatment. We show here that ChoKalpha is constitutively altered in human bladder tumor cells. Furthermore, in vivo murine models, including an orthotopic model to mimic as much as possible the physiological conditions, revealed that increased levels of ChoKalpha potentiate both tumor formation (P< or =0.0001) and aggressiveness of the disease on different end points (P=0.011). Accordingly, increased levels of ChoKalpha significantly reduce survival of mice with bladder cancer (P=0.05). Finally, treatment with a ChoKalpha-specific inhibitor resulted in a significant inhibition of tumor growth (P=0.02) and in a relevant increase in survival (P=0.03).
Hernando
E
E
Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Sarmentero-Estrada
J
J
Koppie
T
T
Belda-Iniesta
C
C
Ramírez de Molina
V
V
Cejas
P
P
Ozu
C
C
Le
C
C
Sánchez
J J
JJ
González-Barón
M
M
Koutcher
J
J
Cordón-Cardó
C
C
Bochner
B H
BH
Lacal
J C
JC
Ramírez de Molina
A
A
D000818:Animals; D045744:Cell Line, Tumor; D002797:Choline Kinase / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness; D015996:Survival Rate; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000473:pathology*
C517212:CHKA protein, human; D002797:Choline Kinase