title: Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways.
abstract: Bioactive phytochemicals can suppress the growth of malignant cells, and investigation of the mechanisms responsible can assist in the identification of novel therapeutic strategies for cancer therapy. Ginger has been reported to exhibit potent anti-cancer effects, although previous reports have often focused on a narrow range of specific compounds. Through a direct comparison of various ginger compounds, we determined that gingerenone A selectively kills cancer cells while exhibiting minimal toxicity toward normal cells. Kinase array screening revealed JAK2 and S6K1 as the molecular targets primarily responsible for gingerenone A-induced cancer cell death. The effect of gingerenone A was strongly associated with relative phosphorylation levels of JAK2 and S6K1, and administration of gingerenone A significantly suppressed tumor growth in vivo. More importantly, the combined inhibition of JAK2 and S6K1 by commercial inhibitors selectively induced apoptosis in cancer cells, whereas treatment with either agent alone did not. These findings provide rationale for dual targeting of JAK2 and S6K1 in cancer for a combinatorial therapeutic approach.
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270, Republic of Korea.
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.affiliation: WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Semi
authors.initials: S
authors.lastname: Lim
authors.affiliation: Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam 461-463, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Mun
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Ki Hyun
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Ramadhar
authors.affiliation: Yuhan Research Institute, Yuhan Corp., Yongin 446-902, Republic of Korea.
authors.forename: Lee
authors.initials: L
authors.lastname: Farrand
authors.affiliation: Program in Biomedical Informatics and Computational Biology, University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Shin
authors.affiliation: Department of Chemistry, Government Sri Krishnarajendra Silver Jubilee Technological Institute, Bangalore 560001, India, World Class Institute, Korea Research Institute of Bioscience and Biotechnology, Ochang 363-883, Korea.
authors.forename: N R
authors.initials: NR
authors.lastname: Thimmegowda
authors.affiliation: WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, jon_clardy@hms.harvard.edu.
authors.forename: Jon
authors.initials: J
authors.lastname: Clardy
authors.affiliation: From the Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, swlee@mgh.harvard.edu.
authors.forename: Sam W
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270, Republic of Korea, WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea, kiwon@snu.ac.kr.
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D036381:Diarylheptanoids / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D036381:Diarylheptanoids; D004791:Enzyme Inhibitors; C000604237:gingerenone A; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1
keywords: JAK2 signaling; S6K1 signaling; anticancer; cancer biology; cell death; cell signaling; chemoprevention; gingerenone A; small molecule