uPA dependent and independent mechanisms of wound healing by C‐phycocyanin

• Published in: Journal of cellular and molecular medicine 2008-12, Vol.12 (6b), p.2691-2703
• Main Authors: Madhyastha, H. K., Radha, K. S., Nakajima, Y., Omura, S., Maruyama, M.
• Format: Article
• Language: English
• Subjects: Algae; Animals; Biotechnology; cdc42 GTP-Binding Protein - metabolism; Cell adhesion & migration; Cell cycle; Cell Cycle - drug effects; Cell Death - drug effects; Cell Line; Cell migration; Cell Movement - drug effects; cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemokines; Chemokines - metabolism; Cloning; Cyclin-Dependent Kinases - metabolism; Cytotoxicity; C‐phycocyanin; Dermis - drug effects; Dermis - pathology; Dietary supplements; Disease Models, Animal; Endothelial cells; Eotaxin; Epithelial cells; Experiments; Extracellular matrix; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; G1 phase; Gene expression; Guanine nucleotide-binding protein; Humans; Inflammation; Injuries; Mice; Models, Biological; Phosphatidylinositol 3-Kinases - metabolism; Phycocyanin - pharmacology; PI‐3K pathway; Protein kinase A; rac1 GTP-Binding Protein - metabolism; RANTES; RNA-mediated interference; Rodents; Software; Studies; U-Plasminogen activator; Ulcers; uPA; Urokinase-Type Plasminogen Activator - metabolism; Wound healing; Wound Healing - drug effects
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/j.1582-4934.2008.00272.x

Wound repair requires both recruitment and well co‐ordinated actions of many cell types including inflammatory cells, endothelial cells, epithelial cells and importantly fibroblast cells. Urokinase‐type plasminogen activator (uPA) system plays a vital role in wound healing phenomenon. We have previously demonstrated that C‐phycocyanin (C‐pc), a biliprotein from blue‐green algae, transcriptionally regulates uPA through cAMP‐dependent protein kinase A (PKA) pathway. To date, a role for C‐pc in wound‐healing scenario is not elucidated. This study was designed to examine the wound‐healing property of C‐pc in relation to fibroblast proliferation and migration. C‐pc increased fibroblast proliferation in a dose‐dependent manner. It also enhanced G1 phase of cell cycle and increased the expressions of cyclin‐dependent kinases 1 and 2, which facilitate cell cycle progression, in a uPA‐independent manner. In vitro wound healing and migration assays revealed the pro‐migratory properties of C‐pc. Short‐interference RNA studies demonstrated that uPA was necessary for C‐pc‐induced fibroblast migration. C‐pc also significantly elevated the expressions of chemokines (MDC, RANTES, Eotaxin, GRO α, ENA78 and TARC) and Rho‐GTPases (Cdc 42 and Rac 1) in a uPA‐dependent manner. Pre‐treatment of C‐pc‐stimulated cells with pharmacological inhibitor of PI‐3K (LY294002) annulled the expression of GTPases implying that Rac 1 and Cdc 42 were induced through PI‐3K pathway. C‐pc‐induced cellular migration towards wounded area was also negatively affected by PI‐3K inhibition. In vivo wound‐healing experiments in mice validated our finding that C‐pc accelerates wound healing. Our data provides conclusive evidence of a novel therapeutic usage for C‐pc as a wound‐healing agent. C‐pc is a food and drug administration (FDA)‐approved health supplement. We believe this compound can also be beneficial in healing of internal wounds, such as ulcers.