title: 6-Shogaol exerts anti-proliferative and pro-apoptotic effects through the modulation of STAT3 and MAPKs signaling pathways.
abstract: 6-shogaol (6SG), one of active ingredients in ginger (Zingiber officinale), is known to exhibit anti-proliferative, anti-metastatic, and pro-apoptotic activities through a mechanism that is not fully elucidated. Because the aberrant activation of STAT3 and MAPKs have been associated with regulation of proliferation, invasion, and metastasis of tumors, we hypothesized that 6SG modulates the activation of STAT3 and MAPKs activation in tumor cells. We found that 6SG strongly inhibited constitutive phosphorylation of STAT3 through inhibition of the activation of upstream JAK2 and c-Src kinases and nuclear translocation of STAT3 on both MDA-MB231 and DU145 cells. Also, 6SG caused the activation of JNK, p38 MAPK, and ERK. Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented 6SG-induced apoptosis. 6SG induced apoptosis as characterized by cleavage of PARP, accumulation of cells in subG1 phase, positive Annexin V binding, down-regulation of STAT3-regulated proteins, and activation of caspase-8, -9, -3 in both MDA-MB231 cells. Compared with other analogues of 6SG, such as 6-gingerol (6G), 8-gingerol (8G), and 10-gingerol (10G), 6SG was found to be the most potent blocker of STAT3 activation. We observed that the administration of 6SG alone significantly suppressed the growth of the tumor. As compared to the vehicle control, 6SG also suppressed the expression of STAT3-regulated gene products such as Bcl-2, Bcl-xL, and Survivin in tumor tissues. Overall, these findings suggest that 6SG can interfere with multiple signaling cascades involved in tumorigenesis and can be used as a potential therapeutic candidate for both the prevention and treatment of cancer.
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Sung-Moo
authors: SM
authors: Kim
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Chulwon
authors: C
authors: Kim
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Hang
authors: H
authors: Bae
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Jong Hyun
authors: JH
authors: Lee
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Seung Ho
authors: SH
authors: Baek
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Dongwoo
authors: D
authors: Nam
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Won-Seok
authors: WS
authors: Chung
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Bum Sang
authors: BS
authors: Shim
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Seok-Geun
authors: SG
authors: Lee
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Sung-Hoon
authors: SH
authors: Kim
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, and Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors: Gautam
authors: G
authors: Sethi
authors: College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors: Kwang Seok
authors: KS
authors: Ahn
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000081247:CSK Tyrosine-Protein Kinase; D020169:Caspases / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin; D051020:bcl-X Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; D002396:Catechols; D051034:Inhibitor of Apoptosis Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D051020:bcl-X Protein; C040115:shogaol; D000081247:CSK Tyrosine-Protein Kinase; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019061:src-Family Kinases; C000631346:CSK protein, human; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: 6-Shogaol; MAPKs; STAT3; apoptosis