Asunto(s)
Inhibidores de la Ciclooxigenasa/administración & dosificación , Hamartoma/tratamiento farmacológico , Síndrome de Peutz-Jeghers/tratamiento farmacológico , Animales , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Hamartoma/genética , Hamartoma/prevención & control , Humanos , Ratones , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/prevención & control , Proyectos Piloto , Pronóstico , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Peutz-Jeghers syndrome (PJS) is typically manifested as severe gastrointestinal polyposis. Polyps in PJS patients and in Lkb1(+/-) mice that model PJS polyposis are frequently characterized by elevated cyclooxygenase-2 (COX-2). This study was designed to determine whether COX-2 inhibition would reduce tumor burden in Lkb1(+/-) mice or Peutz-Jeghers patients. METHODS: Genetic interactions between Cox-2 and Lkb1 in polyp formation were analyzed in mice with combined deficiencies in these genes. Pharmacologic inhibition of COX-2 was achieved by supplementing the diet of Lkb1(+/-) mice with 1500 ppm celecoxib between 3.5-10 and 6.5-10 months. In PJS patients, COX-2 was inhibited with a daily dose of 2 x 200 mg celecoxib for 6 months. RESULTS: Total polyp burden in Lkb1(+/-) mice was significantly reduced in a Cox-2(+/-) (53%) and in a Cox-2(-/-) (54%) background. Celecoxib treatment initiating before polyposis (3.5-10 months) led to a dramatic reduction in tumor burden (86%) and was associated with decreased vascularity of the polyps. Late treatment (6.5-10 months) also led to a significant reduction in large polyps. In a pilot clinical study, a subset of PJS patients (2/6) responded favorably to celecoxib with reduced gastric polyposis. CONCLUSIONS: These data establish a role for COX-2 in promoting Peutz-Jeghers polyposis and suggest that COX-2 chemoprevention may prove beneficial in the treatment of PJS.
Asunto(s)
Proteínas Portadoras , Inhibidores de la Ciclooxigenasa/uso terapéutico , Isoenzimas/antagonistas & inhibidores , Síndrome de Peutz-Jeghers/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Sulfonamidas/uso terapéutico , Proteínas Quinasas Activadas por AMP , Proteínas Adaptadoras Transductoras de Señales , Animales , Celecoxib , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Modelos Animales de Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intracelular , Isoenzimas/genética , Isoenzimas/fisiología , Proteínas de la Membrana , Ratones , Ratones Endogámicos C57BL , Microcirculación/efectos de los fármacos , Síndrome de Peutz-Jeghers/enzimología , Síndrome de Peutz-Jeghers/patología , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/fisiología , PirazolesRESUMEN
Inactivating germ-line mutations of LKB1 lead to Peutz-Jeghers syndrome (PJS). We have generated mice heterozygous for a targeted inactivating allele of Lkb1 and found that they develop severe gastrointestinal polyposis. In all cases, the polyps arising in the Lkb1+/- mice were found to be hamartomas that were histologically indistinguishable from polyps resected from PJS patients, indicating that Lkb1+/- mice model human PJS polyposis. No evidence for inactivation of the remaining wild-type Lkb1 allele in Lkb1+/- -associated polyps was observed. Moreover, polyps and other tissues in heterozygote animals exhibited reduced Lkb1 levels and activity, indicating that Lkb1 was haploinsufficient for tumor suppression. Analysis of the molecular mechanisms characterizing Lkb1+/- polyposis revealed that cyclooxygenase-2 (COX-2) was highly up-regulated in murine polyps concomitantly with activation of the extracellular signal-regulated kinases 1 and 2 (Erk1/2). Subsequent examination of a large series of human PJS polyps revealed that COX-2 was also highly up-regulated in the majority of these polyps. These findings thereby identify COX-2 as a potential target for chemoprevention in PJS patients.
Asunto(s)
Proteínas Portadoras , Isoenzimas/biosíntesis , Síndrome de Peutz-Jeghers/enzimología , Síndrome de Peutz-Jeghers/genética , Prostaglandina-Endoperóxido Sintasas/biosíntesis , Proteínas Quinasas Activadas por AMP , Proteínas Adaptadoras Transductoras de Señales , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Factores de Crecimiento Endotelial/metabolismo , Inducción Enzimática , Genes Supresores de Tumor , Heterocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular , Linfocinas/metabolismo , Proteínas de la Membrana , Ratones , Ratones Noqueados , Síndrome de Peutz-Jeghers/tratamiento farmacológico , Síndrome de Peutz-Jeghers/patología , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Germline mutations of the LKB1 tumor suppressor gene lead to Peutz-Jeghers syndrome (PJS), with a predisposition to cancer. LKB1 encodes for a nuclear and cytoplasmic serine/threonine kinase, which is inactivated by mutations observed in PJS patients. Restoring LKB1 activity into cancer cell lines defective for its expression results in a G(1) cell cycle arrest. Here we have investigated molecular mechanisms leading to this arrest. Reintroduced active LKB1 was cytoplasmic and nuclear, whereas most kinase-defective PJS mutants of LKB1 localized predominantly to the nucleus. Moreover, when LKB1 was forced to remain cytoplasmic through disruption of the nuclear localization signal, it retained full growth suppression activity in a kinase-dependent manner. LKB1-mediated G(1) arrest was found to be bypassed by co-expression of the G(1) cyclins cyclin D1 and cyclin E. In addition, the protein levels of the CDK inhibitor p21(WAF1/CIP1) and p21 promoter activity were specifically upregulated in LKB1-transfected cells. Both the growth arrest and the induction of the p21 promoter were found to be p53-dependent. These results suggest that growth suppression by LKB1 is mediated through signaling of cytoplasmic LKB1 to induce p21 through a p53-dependent mechanism.