TF/FVIIa/PAR2 promotes cell proliferation and migration via PKCα and ERK-dependent c-Jun/AP-1 pathway in colon cancer cell line SW620

Abstract

Our previous study has demonstrated that tissue factor-factor VIIa (TF/FVIIa) complex promotes the proliferation and migration of colon cancer cell line SW620 through the activation of protease-activated receptor 2 (PAR2). In the current study, the underlying molecular mechanisms of TF/FVIIa/PAR2 signaling in SW620 cells were further explored, with the focus on the role of activator protein-1 (AP-1) subunit c-Jun. The results revealed that PAR2-AP and FVIIa could upregulate c-Jun expression and c-Jun phosphorylation in SW620 cells in a time-dependent manner. The effect of FVIIa was significantly blocked by anti-TF and anti-PAR2 antibodies. Protein kinase Cα (PKCα) inhibitor safingol and extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor U0126 abrogated the activation of c-Jun. In contrast, Ca(2+) chelators EGTA and thapsigargin, and p38MAPK inhibitor SB203580 had no effect. Suppression of c-Jun/AP-1 activation using a natural inhibitor curcumin decreased the expression of caspase-3, MMP-9, and TF, as well as the proliferation and migration of SW620 cells induced by PAR2-AP or FVIIa. Collectively, our findings suggest that c-Jun/AP-1 activation is required for TF/FVIIa/PAR2-induced SW620 cell proliferation and migration. PKCα and ERK1/2 are located upstream of c-Jun/AP-1 in this signaling pathway. Pharmacological inhibition of this pathway might be a novel strategy for colon cancer therapy.

Tissue Factor: A Conventional or Alternative Target in Cancer Therapy

“…Both TF isoforms play essential and often isoformspecific roles in cancer biology and pathophysiology, i.e., in cancer-related thrombogenicity, metastasis, and angiogenesis (2,8,21,23,30 ). Differential TF isoform functions are suggested to be mediated by isoformspecific signal transduction via PAR-2 or integrins ␣v␤3, respectively (13,23,24 ).…”

“…Differential TF isoform functions are suggested to be mediated by isoformspecific signal transduction via PAR-2 or integrins ␣v␤3, respectively (13,23,24 ).…”

“…Several studies indicate that flTF, asTF, and TF isoform-specific signaling are promising new targets for the treatment of cancer and other human diseases (13,21,23,42,45 ). Moreover, preliminary human studies and clinical trials were done to characterize the therapeutic value of drugs and molecules interacting with TF, its isoforms, and associated signaling pathways, such as a study indicating that indirect inhibition of TF activity by vitamin K antagonists was associated with a reduced risk for cancer development (37 ).…”

“…The proposed mechanisms and aspects of potential pharmacological treatment strategies have been reviewed in detail elsewhere (22 ). flTF has been shown to mediate cell signaling via PAR-2 and downstream signaling proteins, i.e., protein kinase C (PKC) and extracellular signal-regulated kinase 1 and 2 (13,23 ). In this context, Hu et al found that flTF induced cell proliferation and migration of colon cancer cells via PAR-2-mediated signaling (23 ).…”

Effects of Tissue Factor, PAR-2 and MMP-9 Expression on Human Breast Cancer Cell Line MCF-7 Invasion

“…TF has become one of the targets of targeted therapy for breast cancer cells (Cole et al, 2013), and is considered an important aspect of breast cancer research (Santos et al, 2013). Studies have shown that TF and MMP -9 expression is significantly correlated with breast cancer cells in humans and dogs (Zhao et al, 2008;Hu et al, 2013). In human colon cancer cells Wu et al, 2013a;Wu et al, 2013b), TF promotes the invasion and metastasis of tumor cells by upregulating MMP-9 .…”