JNK inhibitor IX restrains pancreatic cancer through p53 and p21

Abstract

Novel treatment options for pancreatic cancer are desperately needed. De-regulated kinases can be regularly detected in pancreatic cancer. Multiple pathway inhibitors were developed to exploit these features, among them selective inhibitors of the c-Jun N-terminal kinase isoforms 1 and 2 (JNK1 and 2). We evaluated the effectiveness of four different JNK inhibitors on pancreatic cancer cell lines. Cell mobility and migration were evaluated in scratch assay and Boyden chamber assay. Mechanism of cell death was analyzed via apoptosis assays in FACS and immunoblotting as well as cell cycle analysis via FACS, and qPCR. JNK2 knockout cells were generated using siRNA transfection. Among the inhibitors, JNK inhibitor IX (JNK-in-IX), designed as specific inhibitor against JNK2 was proven highly effective in inhibiting cell growth, mobility and migration. We were able to show that JNK-in-IX caused DNA damage resulting in G2 arrest mediated through p53 and p21. Interestingly, JNK-in-IX acted independently of its primary target JNK2. In summary, JNK-in-IX was shown highly effective in pancreatic cancer. This study underlines the need for modeling systems in testing therapeutic options as JNK2 was previously not indicated as a potential target.

GPX3 represses pancreatic cancer cell proliferation, migration and invasion, and improves their chemo‑sensitivity by regulating the JNK/c‑Jun signaling pathway

“…Liu et al (31) reported that the Zrt-Irt-like protein 4/zinc finger E-box-binding homeobox 1 axis mediated the resistance of pancreatic tumors to GEM via regulating JNK/c-Jun signaling. Shi et al (26) also demonstrated that IX, a JNK inhibitor, restrained PC via regulating p53 and p21. Therefore, inhibiting JNK/c-Jun signaling may be a practicable approach for alleviating the metastasis and chemoresistance of PC (26,32).…”

“…Shi et al (26) also demonstrated that IX, a JNK inhibitor, restrained PC via regulating p53 and p21. Therefore, inhibiting JNK/c-Jun signaling may be a practicable approach for alleviating the metastasis and chemoresistance of PC (26,32). In the present study, GPX3 overexpression significantly inhibited the activity of JNK/c-Jun signaling.…”

“…JNK, one of the two major MAPK pathways, can regulate the expression of target genes involved in modulating cell survival and apoptosis via activating c-Jun ( 24 , 25 ). Emerging evidence has also suggested that JNK/c-Jun signaling is involved in the development of PC and the chemosensitivity of PC cells ( 25 , 26 ). Previous studies revealed that the phosphorylation of JNK induced the migration and invasion of PC cells.…”

Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors

“…Table 4 shows the inhibitors of SMAD-interacting enzymes (Jun N-terminal kinase (JNK), p38 MAP kinase, AKT, TRAF6, RhoA, PKA) that control non-SMAD noncanonical TGF-β pathways [ 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 , 275 , 276 , 277 , 278 , 279 , 280 , 281 , 282 , 283 , 284 , 285 , 286 , 287 , 288 ]. A potential inhibitor, SP0016125, targets c-Jun N-terminal kinase (JNK) and stimulates TGF-β-induced apoptosis of the RBE human cholangiocarcinoma cell line [ 264 ].…”