Curcumin Derivative C66 Suppresses Pancreatic Cancer Progression through the Inhibition of JNK-Mediated Inflammation

Abstract

Pancreatic adenocarcinoma is by far the deadliest type of cancer. Inflammation is one of the important risk factors in tumor development. However, it is not yet clear whether deterioration in pancreatic cancer patients is related to inflammation, as well as the underlying mechanism. In addition, JNK is abnormally activated in pancreatic cancer cells and the JNK inhibitor C66 reduces the inflammatory microenvironment in the tumor. Therefore, the aim of this study was to evaluate the role of C66 in the proliferation and migration of pancreatic cancer. Our results showed that various inflammatory cytokines, such as IL-1β, IL-6, IL-8, and IL-15, were more expressed in pancreatic cancer than in the matching normal tissue. Furthermore, C66, a curcumin analogue with good anti-inflammatory activity, inhibited the proliferation and migration of pancreatic cancer cells in a dose-dependent manner, and effectively inhibited the expression of the above inflammatory factors. Our previous research demonstrated that C66 prevents the inflammatory response by targeting JNK. Therefore, in this study, JNK activity in pancreatic cancer cells was investigated, revealing that JNK was highly activated, and the treatment with C66 inhibited the phosphorylation of JNK. Next, shJNK was used to knockdown JNK expression in pancreatic cancer cells to further confirm the role of JNK in the proliferation and migration of this tumor, as well as in the inflammatory tumor microenvironment (TME). The results demonstrated that JNK knockdown could significantly inhibit the proliferation and migration of pancreatic cancer. Moreover, the low JNK expression in pancreatic cancer cells significantly inhibited the expression of various inflammatory factors. These results indicated that C66 inhibited the progression of pancreatic cancer through the inhibition of JNK-mediated inflammation.

Baicalin Weakens the Porcine ExPEC-Induced Inflammatory Response in 3D4/21 Cells by Inhibiting the Expression of NF-κB/MAPK Signaling Pathways and Reducing NLRP3 Inflammasome Activation

“…At the same time, BA significantly inhibited the levels of phosphorylated ERK, P38, and JNK in the 3D4/21 cells induced by PCN033 ( Figure 9 ). Our results are consistent with these reports [ 50 , 51 , 52 ].…”

“…BA treatment reduced the high phosphorylation levels of c-Jun N-terminal kinase (JNK), p65, p-38, and ERK1/2 triggered by atherosclerosis [ 50 ]. Recent research reported that azelastine inhibited inflammation induced by LPS by inhibiting the JNK/NF- B pathway [ 51 ], and curcumin derivative C66 suppressed inflammation through inhibition of the JNK pathway [ 52 ]. Our results show that BA significantly inhibited the transcription levels of inflammatory factors c-jun and c-fos in the 3D4/21 cells induced by PCN033 ( Figure 8 ).…”

Role of natural products in tumor therapy from basic research and clinical perspectives

“…Another curcumin derivative, C66, has good anti-inflammatory activity. C66 was shown to inhibit the progression of PC cells via inhibition of JNK-mediated inflammation [212]. Curcumin inhibits ERK-and JNK-mediated EMT in vitro by upregulating TFPI-2, subsequently suppressing the migration and invasion of PC cells [213].…”

The therapeutic potential of natural products for treating pancreatic cancer

“…Curcumin analogue C66 has been reported to inhibit the proliferation and migration of pancreatic cancer in a dose- and time-dependent manner (25–100 μM, 24–72 h, respectively). Further this analogue could inhibit the inflammatory cytokines (IL-1β, IL-6, IL-8, and IL-15) secretion via the inhibition of JNK pathway ( Chen et al, 2022a ). The anti-pancreatic cancer effects and mechanisms of curcumin and its derivatives are described in detail ( Huang et al, 2022 ).…”