c) Serine/threonine protein kinases: CMGC group(MAPK family - ERK1_2; extracellular signal-regulated kinase ½) and associated proteins:i) Cancer cell migration:
Protease-activated receptors (PAR) are G protein-coupled receptors that function as cell-surface sensors for coagulant proteases, as well as other proteases associated with the tumor microenvironment. PAR1 is activated by thrombin whereas the upstream coagulant protease VIIa bound to tissue factor and Xa can activate both PAR1 and PAR2. PAR1 has been implicated in tumor cell growth, migration, and invasion whereas the function of PAR2 in these processes is largely unknown.
Protease-activated receptors (PAR) are G protein-coupled receptors that function as cell-surface sensors for coagulant proteases, as well as other proteases associated with the tumor microenvironment. PAR1 is activated by thrombin whereas the upstream coagulant protease VIIa bound to tissue factor and Xa can activate both PAR1 and PAR2. PAR1 has been implicated in tumor cell growth, migration, and invasion whereas the function of PAR2 in these processes is largely unknown.
Studies with siRNA strongly suggest that PAR2 is critical for MDA-MB-231 and BT549 breast cancer cell migration and invasion towards NIH 3T3 fibroblast conditioned medium. Together, these studies reveal the novel findings that PAR2, a second protease-activated G protein-coupled receptor, has a critical role in breast cancer cell migration and invasion and functions as the endogenous receptor for coagulant proteases VIIa and Xa in these cells (1).
ii) Carcinoma of the prostate (CaP):
- the inhibition of MMP-2 and MMP-9 in DU145 cells by EGCG is mediated via inhibition of phosphorylation of ERK1/2 and p38 pathways, and inhibition of activation of transcription factors c-jun and NF-kappaB. EGCG may play a role in prevention of invasive metastatic processes of both androgen-dependent and -independent prostate carcinoma.
Practical hint: Since fibroblast conditioned medium (FCM) partially mimics in vivo tumor-host microenvironment, DU145 cells were co-cultured in FCM.
ii) Carcinoma of the prostate (CaP):
- the inhibition of MMP-2 and MMP-9 in DU145 cells by EGCG is mediated via inhibition of phosphorylation of ERK1/2 and p38 pathways, and inhibition of activation of transcription factors c-jun and NF-kappaB. EGCG may play a role in prevention of invasive metastatic processes of both androgen-dependent and -independent prostate carcinoma.
Practical hint: Since fibroblast conditioned medium (FCM) partially mimics in vivo tumor-host microenvironment, DU145 cells were co-cultured in FCM.
References:
1 Morris DR etal Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells Cancer Res. 2006 Jan 1;66(1):307-14
2 Vayalil PK etal Treatment of epigallocatechin-3-gallate inhibits matrix metalloproteinases-2 and -9 via inhibition of activation of mitogen-activated protein kinases, c-jun and NF-kappaB in human prostate carcinoma DU-145 cells Prostate. 2004 Apr 1;59(1):33-42.
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