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Keywords:

  • OPN;
  • PI 3'-kinase;
  • Akt;
  • IKK;
  • NFκB;
  • uPA;
  • cell motility

Abstract

Cancer progression depends on an accumulation of metastasis supporting cell signaling molecules that target signal transduction pathways and ultimately gene expression. Osteopontin (OPN) is one such chemokine like metastasis gene which plays a key signaling event in regulating the oncogenic potential of various cancers by controlling cell motility, invasiveness and tumor growth. We have reported that OPN stimulates tumor growth and nuclear factor κB (NFκB)-mediated promatrix metalloproteinase-2 (pro-MMP-2) activation through IκBα/IKK (IκBα kinase) signaling pathway in melanoma cells. Urokinase type plasminogen activator (uPA), a widely acting serine protease degrades the ECM components and plays a pivotal role in cancer progression. However, the molecular mechanism by which upstream kinases regulate the OPN-induced NFκB activation and uPA secretion in human breast cancer cells is not well defined. Here we report that OPN induces the phosphatidylinositol 3'-kinase (PI 3'-kinase) activity and phosphorylation of Akt/PKB (protein kinase B) in highly invasive (MDA-MB-231) and low invasive (MCF-7) breast cancer cells. The OPN-induced Akt phosphorylation was inhibited when cells were transfected with dominant negative mutant of p85 domain of PI 3'-kinase (Δp85) indicating that PI 3'-kinase is involved in Akt phosphorylation. OPN enhances the interaction between IκBα kinase (IKK) and phosphorylated Akt. OPN also induces NFκB activation through phosphorylation and degradation of IκBα by inducing the IKK activity. OPN also enhances uPA secretion, cell motility and ECM-invasion. Furthermore, cells transfected with Δp85 or super-repressor form of IκBα suppressed the OPN-induced uPA secretion and cell motility. Pretreatment of cells with PI 3'-kinase inhibitors or NFκB inhibitory peptide (SN50) reduced the OPN-induced uPA secretion, cell motility and ECM-invasion. Taken together, OPN induces NFκB activity and uPA secretion by activating PI 3'-kinase/Akt/IKK-mediated signaling pathways and further demonstrates a functional molecular link between OPN induced PI 3'-kinase dependent Akt phosphorylation and NFκB-mediated uPA secretion, and all of these ultimately control the motility and invasiveness of breast cancer cells. IUBMB Life, 57: 441-447, 2005