Inhibition of c-Jun NH2-terminal kinase switches Smad3 signaling from oncogenesis to tumor- suppression in rat hepatocellular carcinoma

Abstract

Transforming growth factor beta (TGF-␤) signaling involves both tumor-suppression and oncogenesis. TGF-␤ activates the TGF-␤ type I receptor (T␤RI) and c-Jun N-terminal kinase (JNK), which differentially phosphorylate the mediator Smad3 to become COOHterminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). T␤RI-dependent pSmad3C transmits a tumor-suppressive TGF-␤ signal, while JNK-dependent pSmad3L promotes carcinogenesis in human chronic liver disorders. The aim of this study is to elucidate how SP600125, a JNK inhibitor, affected rat hepatocellular carcinoma (HCC) development, while focusing on the domain-specific phosphorylation of Smad3. The rats received subcutaneous injections of either SP600125 or vehicle 11 times weekly together with 100 ppm N-diethylnitrosamine (DEN) administration for 56 days and were sacrificed in order to evaluate HCC development 28 days after the last DEN administration. The number of tumor nodules greater than 3 mm in diameter and the liver weight/ body weight ratio were significantly lower in the SP600125-treated rats than those in the vehicle-treated rats (7.9 ؎ 0.8 versus 17.7 ؎ 0.9: P < 0.001; 6.3 ؎ 1.2 versus 7.1 ؎ 0.2%: P < 0.05). SP600125 significantly prolonged the median survival time in rats with DENinduced HCC (113 versus 97 days: log-rank P ‫؍‬ 0.0018). JNK/pSmad3L/c-Myc was enhanced in the rat hepatocytes exposed to DEN. However, T␤RI/pSmad3C/p21 WAF1 was impaired as DEN-induced HCC developed and progressed. The specific inhibition of JNK activity by SP600125 suppressed pSmad3L/c-Myc in the damaged hepatocytes and enhanced pSmad3C/p21 WAF1 , acting as a tumor suppressor in normal hepatocytes. Conclusion: Administration of SP600125 to DEN-treated rats shifted hepatocytic Smad3-mediated signal from oncogenesis to tumor suppression, thus suggesting that JNK could be a therapeutic target of human HCC development and progression.

PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway

“…[28][29][30] It was also shown that inhibition of C-terminal phosphorylation of Smad3 by JNK shifts Smad3-mediated signaling from oncogenesis to tumor suppression in rat hepatocellular carcinoma. 31 These findings suggest that multiple genes and signaling factors might be involved in the oncogenic conversion of TGF-β1 function in different tumor types.…”

Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer

“…Importantly, JNK1 is phosphorylated in human HCC samples (56). Direct evidence for the idea that JNK could be a promising drug target was provided by the findings that administration of the JNK inhibitor SP600125 to Cyld-deficient mice or DEN-treated rats blocked the development of HCC (46,57). SP600125 has also been shown to sensitize tumor cells, but not normal hepatocytes, to TRAIL, a major mediator of acquired immune tumor surveillance (58).…”

TGF-β signal shifting between tumor suppression and fibro-carcinogenesis in human chronic liver diseases

“…In actively growing hepatocytes, intracellular phosphorylation at Smad3L is increased (Fig. 2a, upper middle panel) [50][51][52]. Translocated to the nucleus, TNF-a-induced pSmad3L stimulates c-Myc transcription [53], which increases proliferation of hepatocytes and opposes the cytostatic action of the pSmad3C pathway [7].…”