title: Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells.
abstract: BACKGROUND
  Signal transducer and activator of transcription 3 (STAT3) is persistently activated in squamous cell carcinoma of the head and neck (SCCHN) and can cause uncontrolled cellular proliferation and division.
  
  
  OBJECTIVE
  Thus, its targeted abrogation could be an effective strategy to reduce the risk of SCCHN. Resveratrol is known for its anti-cancer efficacy in a variety of cancer models.
  
  
  METHODS
  The effect resveratrol on STAT3 activation, associated protein kinases, phosphatases, cellular proliferation and apoptosis was investigated.
  
  
  METHODS
  We evaluated the effect of resveratrol on STAT3 signaling cascade and its regulated functional responses in SCCHN cells.
  
  
  RESULTS
  We found that HN3 and FaDu cells expressed strongly phosphorylated STAT3 on both tyrosine 705 and serine 727 residues as compared to other SCCHN cells. The phosphorylation was completely suppressed by resveratrol in FaDu cells, but not substantially in HN3 cells. STAT3 suppression was mediated through the inhibition of activation of upstream JAK2, but not of JAK1 and Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the resveratrol-induced down-regulation of STAT3, thereby indicating a critical role for a PTP. We also found that resveratrol induced the expression of the SOCS-1 protein and mRNA. Further, deletion of SOCS-1 gene by siRNA suppressed the induction of SOCS-1, and reversed the inhibition of STAT3 activation. Resveratrol down-regulated various STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced the cell accumulation in the sub-G1 phase and caused apoptosis. Beside, this phytoalexin also exhibited the enhancement of apoptosis when combined with ionizing radiation treatment.
  
  
  CONCLUSIONS
  Our results suggest that resveratrol blocks STAT3 signaling pathway through induction of SOCS-1, thus attenuating STAT3 phosphorylation and proliferation in SCCHN cells.
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
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 130-701, Republic of Korea.
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Ko
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Hanwool
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, 23 Kyungheedae-ro, Dongdaemoon-gu, Seoul 130-872, Republic of Korea.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Jung
authors.affiliation: Department of Radiation Oncology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, 23 Kyungheedae-ro, Dongdaemoon-gu, Seoul 130-872, Republic of Korea.
authors.forename: Moonkyoo
authors.initials: M
authors.lastname: Kong
authors.affiliation: Department of Oral & Maxillofacial Surgery, Kyung Hee University Dental Hospital, Kyung Hee University School of Dentistry, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-872, Republic of Korea.
authors.forename: Jung-woo
authors.initials: JW
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Junhee
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
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.
authors.forename: M E
authors.initials: ME
authors.lastname: Zayed
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
authors.forename: Sulaiman Ali
authors.initials: SA
authors.lastname: Alharbi
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
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 130-701, Republic of Korea.
authors.forename: Bum Sang
authors.initials: BS
authors.lastname: Shim
authors.affiliation: Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117600, Singapore.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea.
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 130-701, Republic of Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Um
authors.affiliation: College of Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Republic of Korea. Electronic address: ksahn@khu.ac.kr.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077185:Resveratrol; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013267:Stilbenes / Q000494:pharmacology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D011838:Radiation-Sensitizing Agents; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D019061:src-Family Kinases; D000077185:Resveratrol
keywords: Resveratrol; SOCS-1; STAT3; Squamous cell carcinoma of the head and neck