title: Blueberry inhibits invasion and angiogenesis in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral squamous cell carcinogenesis in hamsters via suppression of TGF-β and NF-κB signaling pathways.
abstract: Aberrant activation of oncogenic signaling pathways plays a pivotal role in tumor initiation and progression. The purpose of the present study was to investigate the chemopreventive and therapeutic efficacy of blueberry in the hamster buccal pouch (HBP) carcinogenesis model based on its ability to target TGF-β, PI3K/Akt, MAPK and NF-κB signaling and its impact on invasion and angiogenesis. Squamous cell carcinomas were induced in the HBP by 7,12-dimethylbenz[a]anthracene (DMBA). The effect of blueberry on the oncogenic signaling pathways and downstream events was analyzed by quantitative real-time PCR and immunoblotting. Experiments with the ECV304 cell line were performed to explore the mechanism by which blueberry regulates angiogenesis. Blueberry supplementation inhibited the development and progression of HBP carcinomas by abrogating TGF-β and PI3K/Akt pathways. Although blueberry failed to influence MAPK, it suppressed NF-κB activation by preventing nuclear translocation of NF-κB p65. Blueberry also modulated the expression of the oncomiR miR-21 and the tumor suppressor let-7. Collectively, these changes induced a shift to an anti-invasive and anti-angiogenic phenotype as evidenced by downregulating matrix metalloproteinases and vascular endothelial growth factor. Blueberry also inhibited angiogenesis in ECV304 cells by suppressing migration and tube formation. The results of the present study suggest that targeting oncogenic signaling pathways that influence acquisition of cancer hallmarks is an effective strategy for chemointervention. Identification of modulatory effects on phosphorylation, intracellular localization of oncogenic transcription factors and microRNAs unraveled by the present study as key mechanisms of action of blueberry is critical from a therapeutic perspective.
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
authors.forename: Abdul Basit
authors.initials: AB
authors.lastname: Baba
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
authors.forename: Jaganathan
authors.initials: J
authors.lastname: Kowshik
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Krishnaraj
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
authors.forename: Josephraj
authors.initials: J
authors.lastname: Sophia
authors.affiliation: Laboratory of Vascular Biology, Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India.
authors.forename: Madhulika
authors.initials: M
authors.lastname: Dixit
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India. Electronic address: s_nagini@yahoo.com.
authors.forename: Siddavaram
authors.initials: S
authors.lastname: Nagini
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D029798:Blueberry Plants / Q000737:chemistry*; D002273:Carcinogens / Q000633:toxicity; D002461:Cell Line, Transformed; D019587:Dietary Supplements; D005612:Freeze Drying; D005638:Fruit / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008647:Mesocricetus; D009062:Mouth Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018307:Neoplasms, Squamous Cell / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001551:Benz(a)Anthracenes; D002273:Carcinogens; D009363:Neoplasm Proteins; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D015127:9,10-Dimethyl-1,2-benzanthracene
keywords: Angiogenesis; Blueberry; Chemoprevention; Invasion; NF-κB; TGF-β