Journal of Bioequivalence & Bioavailability

Mechanism of elastin mediated angiogenic signaling regulation by hexastatin

4^th World Congress on Bioavailability and Bioequivalence: Pharmaceutical R&D Summit

May 20-22, 2013 DoubleTree by Hilton, Beijing, China

Sudhakar Akul Yakkanti

AcceptedAbstracts: J Bioequiv Availab

Abstract:

Cancer is currently one of the most prevalent causes of human deaths in the world. Current therapeutic options aim only to slow the progression of cancer disease. Therefore, a renewed effort must be made to identify relevant endogenous cancer inhibitors that could be exploited as therapeutic drugs. We identified endogenous anti-cancer molecules, which are released from extracellular matrix (ECM) and were identified as angioinhibitors of tumor growth. These endogenous angioinhibitory proteins bind to the cell surface molecules and transduce the signaling & regulate angiogenesis. Thus, cell surface molecules serve as transmembrane linkers between the ECM and cytoskeleton for outside-in signaling. One such endogenous molecule, Hexastatin, a 26-kDa protein from the C-terminal non-collagenous domain of alpha6 type IV collagen was identified as an inhibitor of angiogenesis but is mediated signaling is not yet known. Our findings suggests that Hexastatin interacting with cell surface molecules and inhibiting laminin mediated angiogenesis by inhibiting phosphorylation of FAK/PI-3K/Akt/mTOR and prevents MT1-MMP expression that leads to endothelial cell migration and tube formation. Further, we also demonstrated that hexastatin inhibits hypoxia induced pro-inflammatory molecules via FAK/Akt pathway, leading to inhibition of tumor angiogenesis and tumor growth both in-vitro and in-vivo.

Biography :

Cancer is currently one of the most prevalent causes of human deaths in the world. Current therapeutic options aim only to slow the progression of cancer disease. Therefore, a renewed effort must be made to identify relevant endogenous cancer inhibitors that could be exploited as therapeutic drugs. We identified endogenous anti-cancer molecules, which are released from extracellular matrix (ECM) and were identified as angioinhibitors of tumor growth. These endogenous angioinhibitory proteins bind to the cell surface molecules and transduce the signaling & regulate angiogenesis. Thus, cell surface molecules serve as transmembrane linkers between the ECM and cytoskeleton for outside-in signaling. One such endogenous molecule, Hexastatin, a 26-kDa protein from the C-terminal non-collagenous domain of alpha6 type IV collagen was identified as an inhibitor of angiogenesis but is mediated signaling is not yet known. Our findings suggests that Hexastatin interacting with cell surface molecules and inhibiting laminin mediated angiogenesis by inhibiting phosphorylation of FAK/PI-3K/Akt/mTOR and prevents MT1-MMP expression that leads to endothelial cell migration and tube formation. Further, we also demonstrated that hexastatin inhibits hypoxia induced pro-inflammatory molecules via FAK/Akt pathway, leading to inhibition of tumor angiogenesis and tumor growth both in-vitro and in-vivo.