Delphinidin inhibits cell proliferation and invasion via modulation of Met receptor phosphorylation.
The HGF/Met signaling pathway is deregulated in majority of cancers and is associated with poor prognosis in breast cancer. Delphinidin, present in pigmented fruits and vegetables possesses potent anti-oxidant, anti-inflammatory and anti-angiogenic properties. Here, we assessed the anti-proliferative and anti-invasive effects of delphinidin on HGF-mediated responses in the immortalized MCF-10A breast cell line. Treatment of cells with delphinidin prior to exposure to exogenous HGF resulted in the inhibition of HGF-mediated (i) tyrosyl-phosphorylation and increased expression of Met receptor, (ii) phosphorylation of downstream regulators such as FAK and Src and (iii) induction of adaptor proteins including paxillin, Gab-1 and GRB-2. In addition, delphinidin treatment resulted in significant inhibition of HGF-activated (i) Ras-ERK MAPKs and (ii) PI3K/AKT/mTOR/p70S6K pathways. Delphinidin was found to repress HGF-activated NFkappaB transcription with a decrease in (i) phosphorylation of IKKalpha/beta and IkappaBalpha, and (ii) activation and nuclear translocation of NFkappaB/p65. Inhibition of HGF-mediated membrane translocation of PKCalpha as well as decreased phosphorylation of STAT3 was further observed in delphinidin treated cells. Finally, decreased cell viability of Met receptor expressing breast cancer cells treated with delphinidin argues for a potential role of the agent in the prevention of HGF-mediated activation of various signaling pathways implicated in breast cancer.
Syed
Deeba N
DN
Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
Afaq
Farrukh
F
Sarfaraz
Sami
S
Khan
Naghma
N
Kedlaya
Rajendra
R
Setaluri
Vijayasaradhi
V
Mukhtar
Hasan
H
D000872:Anthocyanins / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D005260:Female; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000872:Anthocyanins; D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; C017185:delphinidin