Piperine inhibits IL-1β-induced IL-6 expression by suppressing p38 MAPK and STAT3 activation in gastric cancer cells.

Abstract

Piperine, a kind of natural alkaloid found in peppers, has been reported to exhibit anti-oxidative and anti-tumor activities, both in vitro and in vivo. Interleukin-6 (IL-6) is an important cytokine that activates the signal transduction, promotes tumor cell metastasis, and induces malignancy, including in gastric cancer. However, the effects of piperine on IL-6 expression in gastric cancer cells have not yet been well defined. In this study, we investigated the effects of piperine on the IL-6 expression, and examined the underlying signaling pathways via RT-PCR, promoter studies and Western blotting in human gastric cancer TMK-1 cells. Our results showed that piperine inhibited interleukin-1β (IL-1β)-induced IL-6 expression in a dose-dependent manner. In addition, piperine also inhibited IL-6 promoter activity. Experiments with mitogen-activated protein kinase (MAPK) inhibitors and dominant negative mutant p38 MAPK indicated that p38 MAPK was essential for IL-6 expression in the TMK-1 cells. Additionally, signal transducer and activator of transcription 3 (STAT3) was also involved in the IL-1β-induced IL-6 expression in gastric cancer cells. Piperine inhibited IL-1β-induced p38 MAPK and STAT3 activation and, in turn, blocked the IL-1β-induced IL-6 expression. Furthermore, gastric cancer cells pretreated with IL-1β showed markedly enhanced invasiveness, which was partially abrogated by treatment with IL-6 siRNA, piperine, and inhibitors of p38 MAPK and STAT3. These results suggest that piperine may exert at least part of its anti-cancer effect by controlling IL-6 expression through the suppression of p38 MAPK and STAT3.

• Authors: Yong Xia, Pham Ngoc Khoi, Hyun Joong Yoon, Sen Lian, Young Eun Joo, Kee Oh Chay, Kyung Keun Kim, Young Do Jung
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 398 Issue 1-2 Pg. 147-56 (Jan 2015) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 25234193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkaloids
• Benzodioxoles
• Enzyme Inhibitors
• Imidazoles
• Interleukin-1beta
• Interleukin-6
• Piperidines
• Polyunsaturated Alkamides
• Pyridines
• STAT3 Transcription Factor
• p38 Mitogen-Activated Protein Kinases
• UDPglucose 4-Epimerase
• SB 203580
• piperine

Topics

• Alkaloids (pharmacology)
• Benzodioxoles (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Cell Movement (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Imidazoles (pharmacology)
• Interleukin-1beta (pharmacology)
• Interleukin-6 (genetics, metabolism)
• Mutation
• Neoplasm Invasiveness
• Piperidines (pharmacology)
• Polyunsaturated Alkamides (pharmacology)
• Pyridines (pharmacology)
• RNA Interference
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (metabolism)
• Stomach Neoplasms (genetics, metabolism, pathology)
• UDPglucose 4-Epimerase (antagonists & inhibitors)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)