title: 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.affiliation: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, 501-190, Republic of Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.forename: Pham Ngoc
authors.initials: PN
authors.lastname: Khoi
authors.forename: Hyun Joong
authors.initials: HJ
authors.lastname: Yoon
authors.forename: Sen
authors.initials: S
authors.lastname: Lian
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Joo
authors.forename: Kee Oh
authors.initials: KO
authors.lastname: Chay
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
authors.forename: Young Do
authors.initials: YD
authors.lastname: Jung
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014534:UDPglucose 4-Epimerase / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D053583:Interleukin-1beta; D015850:Interleukin-6; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011725:Pyridines; D050796:STAT3 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D014534:UDPglucose 4-Epimerase; C093642:SB 203580; C008922:piperine