RESUMO
Vasculogenic mimicry (VM) is the formation of a blood supply system that confers aggressive and metastatic properties to tumors and correlates with a poor prognosis in cancer patients. Thus, the inhibition of VM is considered an effective approach for cancer treatment, although such a mechanism remains poorly described. In the present study, we examined methionine aminopeptidase2 (MetAP2), a key factor of angiogenesis, and demonstrated that it is pivotal for VM, using pharmacological and genetic approaches. Fumagillin and TNP470, angiogenesis inhibitors that target MetAP2, significantly suppressed VM in various human cancer cell lines. We established MetAP2knockout (KO) human fibrosarcoma HT1080 cells using the CRISPR/Cas9 system and found that VM was attenuated in these cells. Furthermore, reexpression of wildtype MetAP2 restored VM in the MetAP2KO HT1080 cells, but the substitution of D251, a conserved amino acid in MetAP2, failed to rescue the VM. Collectively, our results demonstrate that MetAP2 is critical for VM in human cancer cells and suggest fumagillin and TNP470 as potent VMsuppressing agents.
Assuntos
Aminopeptidases/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Cicloexanos/farmacologia , Ácidos Graxos Insaturados/farmacologia , Metaloendopeptidases/efeitos dos fármacos , Metionil Aminopeptidases/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , O-(Cloroacetilcarbamoil)fumagilol/farmacologia , Aminopeptidases/genética , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Fibrossarcoma/tratamento farmacológico , Técnicas de Silenciamento de Genes , Humanos , Metaloendopeptidases/genética , Metionil Aminopeptidases/genética , Neovascularização Patológica/genética , Sesquiterpenos/farmacologiaRESUMO
The ciliopathies Bardet-Biedl syndrome and Alström syndrome are genetically inherited pleiotropic disorders with hyperphagia and obesity as primary clinical features. Methionine aminopeptidase 2 inhibitors (MetAP2i) have been shown in preclinical and clinical studies to reduce food intake, body weight, and adiposity. Here, we investigated the effects of MetAP2i administration in a mouse model of ciliopathy produced by conditional deletion of the Thm1 gene in adulthood. Thm1 conditional knockout (cko) mice showed decreased hypothalamic proopiomelanocortin expression as well as hyperphagia, obesity, metabolic disease, and hepatic steatosis. In obese Thm1-cko mice, 2-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied by decreased levels of blood glucose, insulin, and leptin. Further, MetAP2i reduced gonadal adipose depots and adipocyte size and improved liver morphology. This is the first report to our knowledge of MetAP2i reducing hyperphagia and body weight and ameliorating metabolic indices in a mouse model of ciliopathy. These results support further investigation of MetAP2 inhibition as a potential therapeutic strategy for ciliary-mediated forms of obesity.