HGF-Induced PKCζ Activation Increases Functional CXCR4 Expression in Human Breast Cancer Cells

Abstract

The chemokine receptor CXCR4 and its ligand CXCL12 have been shown to mediate the metastasis of many malignant tumors including breast carcinoma. Interaction between hepatocyte growth factor (HGF) and the Met receptor tyrosine kinase mediates development and progression of cancers. HGF is able to induce CXCR4 expression and contributes to tumor cell invasiveness in breast carcinoma. However, the mechanism of the CXCR4 expression modulated by c-Met-HGF axis to enhance the metastatic behavior of breast cancer cells is still unclear. In this study, we found that HGF induced functional CXCR4 receptor expression in breast cancer cells. The effect of HGF was specifically mediated by PKCζ activity. After transfection with PKCζ-siRNA, the phosphorylation of PKCζ and CXCR4 was abrogated in breast cancer cells. Interference with the activation of Rac1, a downstream target of HGF, prevented the HGF-induced increase in PKCζ activity and CXCR4 levels. The HGF-induced, LY294002-sensitive translocation of PKCζ from cytosol to plasma membrane indicated that HGF was capable of activating PKCζ, probably via phosphoinositide (PI) 3-kinases. HGF treatment also increased MT1-MMP secretion. Inhibition of PKCζ, Rac-1 and phosphatidylinositol 3-kinase may attenuate MT1-MMP expression in cells exposed to HGF. Functional manifestation of the effects of HGF revealed an increased ability for migration, chemotaxis and metastasis in MDA-MB-436 cells in vitro and in vivo. Our findings thus provided evidence that the process of HGF-induced functional CXCR4 expression may involve PI 3-kinase and atypical PKCζ. Moreover, HGF may promote the invasiveness and metastasis of breast tumor xenografts in BALB/c-nu mice via the PKCζ-mediated pathway, while suppression of PKCζ by RNA interference may abrogate cancer cell spreading.

Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism

“…PKCζ has been implicated in the invasive phenotype of human cancers [36], [37], [38]. RNAi-mediated, specific inhibition of PKCζ reduces breast cancer and glioblastoma cell invasion in vitro [37], [38] and reduces prostate cancer cell invasion in vitro and in vivo [36].…”

“…RNAi-mediated, specific inhibition of PKCζ reduces breast cancer and glioblastoma cell invasion in vitro [37], [38] and reduces prostate cancer cell invasion in vitro and in vivo [36]. Interestingly, each of these reports attributes PKCζ to a distinct invasive signaling pathway, suggesting a broad role for PKCζ in cancer cell invasion [36], [37], [38]. Consistent with the phenotype observed in other cancers, we determined that inhibition of PKCζ expression not only inhibited the transformed growth of pancreatic cancer cells, but also repressed their invasive potential in vitro.…”

HGF–MET Cascade, a Key Target for Inhibiting Cancer Metastasis: The Impact of NK4 Discovery on Cancer Biology and Therapeutics

“…Such an endocrine pathway is required for moving cells to determine the homing sites. Of note, HGF enhances CXCR4 expression by cancer cells [51]. Furthermore, HGF enhances the ability of SDF1 to promote cancer invasion [52].…”

Alpha-fetoprotein activates AKT/mTOR signaling to promote CXCR4 expression and migration of hepatoma cells

“…Phillips et al[28] indicated that epidermal growth factor and hypoxia promoted CXCR4 expression via PI3K/AKT/mTOR pathway in non-small cell lung cancer. Huang et al[29] also reported that the PI3K/AKT pathway was involved in CXCR4 expression and the hepatocyte growth factor-induced activation of protein kinase C-ζ in human breast cancer cells. Moreover, Dubrovska et al[30] demonstrated the direct regulation of CXCR4 expression by the PI3K pathway and thus implied a mutually positive regulatory feedback loop between the PI3K/AKT and CXCR4/CXCL12 signaling pathways, which are both important for cancer metastasis.…”