title: Ginkgolic Acid C 17:1, Derived from Ginkgo biloba Leaves, Suppresses Constitutive and Inducible STAT3 Activation through Induction of PTEN and SHP-1 Tyrosine Phosphatase.
abstract: Ginkgolic acid C 17:1 (GAC 17:1) extracted fromGinkgo bilobaleaves, has been previously reported to exhibit diverse antitumor effect(s) through modulation of several molecular targets in tumor cells, however the detailed mechanism(s) of its actions still remains to be elucidated. Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor that regulates various critical functions involved in progression of diverse hematological malignancies, including multiple myeloma, therefore attenuating STAT3 activation may have a potential in cancer therapy. We determined the anti-tumor mechanism of GAC 17:1 with respect to its effect on STAT3 signaling pathway in multiple myeloma cell lines. We found that GAC 17:1 can inhibit constitutive activation of STAT3 through the abrogation of upstream JAK2, Src but not of JAK1 kinases in U266 cells and also found that GAC can suppress IL-6-induced STAT3 phosphorylation in MM.1S cells. Treatment of protein tyrosine phosphatase (PTP) inhibitor blocked suppression of STAT3 phosphorylation by GAC 17:1, thereby indicating a critical role for a PTP. We also demonstrate that GAC 17:1 can induce the substantial expression of PTEN and SHP-1 at both protein and mRNA level. Further, deletion ofPTENandSHP-1genes by siRNA can repress the induction of PTEN and SHP-1, as well as abolished the inhibitory effect of drug on STAT3 phosphorylation. GAC 17:1 down-regulated the expression of STAT3 regulated gene products and induced apoptosis of tumor cells. Overall, GAC 17:1 was found to abrogate STAT3 signaling pathway and thus exert its anticancer effects against multiple myeloma cells.
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. baeksh@woosuk.ac.kr.|College of Korean Medicine, Woosuk University, 46 Eoeun-ro, Wansan-gu, Jeonju-si, Jeollabuk-do 54987, Korea. baeksh@woosuk.ac.kr.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Baek
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. 88milkyway@hanmail.net.
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. sunny10526@nate.com.
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. gokjh1647@gmail.com.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Ko
authors.affiliation: Department of Radiation Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Korea. rshgood@hanmail.net.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Ryu
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. seokgeun@khu.ac.kr.
authors.forename: Seok-Geun
authors.initials: SG
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. wmyang@khu.ac.kr.
authors.forename: Woong Mo
authors.initials: WM
authors.lastname: Yang
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. jyum@khu.ac.kr.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Um
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia. dr.arunmicro@gmail.com.
authors.forename: Arunachalam
authors.initials: A
authors.lastname: Chinnathambi
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia. sharbi@ksu.edu.sa.
authors.forename: Sulaiman Ali
authors.initials: SA
authors.lastname: Alharbi
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia. phcgs@nus.edu.sg.|School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6009, Australia. phcgs@nus.edu.sg.|Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore. phcgs@nus.edu.sg.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea. ksahn@khu.ac.kr.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020441:Ginkgo biloba / Q000737:chemistry*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry*; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000819:agonists*; D012459:Salicylates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D015850:Interleukin-6; D010936:Plant Extracts; D050796:STAT3 Transcription Factor; D012459:Salicylates; C112485:ginkgolic acid; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D051059:PTEN Phosphohydrolase
keywords: PTEN; SHP-1; STAT3; apoptosis; ginkgolic acid C 17:1