RESUMEN
BACKGROUND AND AIMS: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of the c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and therefore the key downstream effectors of this pathway, remain unknown for their applicability as therapeutic targets. Our aim was to obtain a better mechanistic understanding of the role of JNK signaling in ICC that could open up therapeutic opportunities. APPROACH AND RESULTS: Using loss-of-function and gain-of-function studies in vitro and in vivo, we show that activation of the JNK pathway promotes ICC cell proliferation by affecting the protein stability of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), a key driver of tumorigenesis. PIN1 is highly expressed in ICC primary tumors, and its expression positively correlates with active JNK. Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. Moreover, pharmacological inhibition of PIN1 through all-trans retinoic acid, a Food and Drug Administration-approved drug, impairs the growth of both cultured and xenografted ICC cells. CONCLUSIONS: Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation through PIN1 inhibition.
Asunto(s)
Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/metabolismo , Carcinogénesis/metabolismo , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Animales , Antineoplásicos/administración & dosificación , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 9 Activada por Mitógenos/genética , Peptidilprolil Isomerasa de Interacción con NIMA/antagonistas & inhibidores , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Fosforilación/efectos de los fármacos , Fosforilación/genética , ARN Interferente Pequeño/genética , Tretinoina/administración & dosificación , Carga Tumoral/efectos de los fármacos , Carga Tumoral/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A marked increase in the rate of glycolysis is a key event in the pathogenesis of hepatocellular carcinoma (HCC), the main type of primary liver cancer. Liver cirrhosis is considered to be a key player in HCC pathogenesis as it precedes HCC in up to 90% of patients. Intriguingly, the biochemical events that underlie the progression of cirrhosis to HCC are not well understood. In this study, we examined the expression profile of metabolic gene transcripts in liver samples from patients with HCC and patients with cirrhosis. We found that gene expression of glycolytic enzymes is up-regulated in precancerous cirrhotic livers and significantly associated with an elevated risk for developing HCC. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in HCC compared to normal livers but remain unchanged in cirrhosis. Our findings suggest that key glycolytic enzymes such as hexokinase 2 (HK2), aldolase A (ALDOA), and pyruvate kinase M2 (PKM2) may represent potential markers and molecular targets for early detection and chemoprevention of HCC.
