title: Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer.
abstract: Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT-3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention.
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India.
authors.forename: J
authors.initials: J
authors.lastname: Kowshik
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India.
authors.forename: Abdul Basit
authors.initials: AB
authors.lastname: Baba
authors.affiliation: Laboratory of Vascular Biology, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tami Nadu, India.
authors.forename: Hemant
authors.initials: H
authors.lastname: Giri
authors.affiliation: Medicinal Chemistry Research Division, Vishnu Institute of Pharmaceutical Education and Research, Narsapur, India.
authors.forename: G
authors.initials: G
authors.lastname: Deepak Reddy
authors.affiliation: Laboratory of Vascular Biology, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tami Nadu, India.
authors.forename: Madhulika
authors.initials: M
authors.lastname: Dixit
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India.
authors.forename: Siddavaram
authors.initials: S
authors.lastname: Nagini
mesh_terms: D000818:Animals; D006224:Cricetinae; D053612:Janus Kinases / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D024341:Xanthophylls / Q000627:therapeutic use
chemical_list: D050796:STAT3 Transcription Factor; D024341:Xanthophylls; C005948:astaxanthine; D053612:Janus Kinases