RESUMO
Choline kinase is overexpressed in human breast, lung, colorectal, and prostate tumors, a finding that suggests the involvement of this enzyme in carcinogenesis. Here we show that overexpression of choline kinase induce oncogenic transformation of human embryo kidney fibroblasts and canine epithelial Madin-Darby canine kidney cells. Choline kinase lays downstream of RhoA signaling and is activated through ROCK kinase, one of the best-characterized RhoA effectors. In keeping with this, coexpression of RhoA and choline kinase potentiates both anchorage independent growth and tumorigenesis. Finally, choline kinase-mediated transformation is sensitive to MN58b, a well-characterized specific choline kinase inhibitor. These results provide the definitive evidence that choline kinase has oncogenic properties and that choline kinase inhibition constitutes a novel valid antitumor strategy.
Assuntos
Transformação Celular Neoplásica/metabolismo , Colina Quinase/genética , Proteína rhoA de Ligação ao GTP/fisiologia , Animais , Transformação Celular Neoplásica/genética , Colina Quinase/antagonistas & inibidores , Colina Quinase/metabolismo , Cães , Ativação Enzimática , Humanos , Camundongos , Camundongos Nus , Células NIH 3T3 , Oncogenes , Ratos , Proteína cdc42 de Ligação ao GTP/genética , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteína cdc42 de Ligação ao GTP/fisiologia , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/fisiologia , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
The compound 6a is a novel bisoxazol derivative with high cytotoxic properties in vitro against different human tumor-derived cell lines and with similar efficiency against epithelial, haematopoietic and mesenchymal tumor cells. Although the molecular mechanism is not yet fully defined, cell cycle analysis revealed that 6a induces efficiently G0/G1 phase arrest in colon adenocarcinoma HT-29 cells in a dose- and time-dependent manner. Induction of cell death is observed, a possible explanation for the antiproliferative profile of the molecule. The compound was well tolerated at doses that allowed to examine its antitumor activity against human xenografts of the HT-29 cell line implanted s.c. in nude mice. Treatment of mice with 4 mg/kg of the compound resulted in a 60% inhibition of tumor growth. These observations support the use of 6a for the generation of more potent derivatives that could be used as new anticancer agents.