Inhibition by Platelet-activating Factor of Src- and Hepatocyte Growth Factor-dependent Invasiveness of Intestinal and Kidney Epithelial Cells

Phosphatidylinositol 3-kinase/Akt regulates the balance between plasminogen activator inhibitor-1 and urokinase to promote migration of SKOV-3 ovarian cancer cells

“…By contrast, expression of constitutively active Akt caused the opposite effects on SKOV-3 cells: an increase in phosphorylated Akt levels correlated with a decrease in PAI-1 expression and an increase in wound-induced migration. The changes in SKOV-3 cell migration that accompanied the increase (constitutively active Akt adenovirus) or decrease (LY294002 and wortmannin treatment, Akt siRNA) in active Akt levels were similar to previously published studies [11][12][13][14][15][36][37][38][39][40][41]. It will be important to further these observations using different ovarian cancer cell lines, especially those that are not dependent on PI3K/Akt for migration and invasion.…”

“…The PI3K/Akt cell signaling pathway is implicated in cell migration and invasion [9][10][11]. The PI3K/Akt pathway regulates uPA expression; selective inhibition of the PI3K/Akt pathway in numerous cell types decreases uPA expression and/ or activity with a subsequent decrease in cell invasion [12][13][14].…”

Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho–Rho kinase axis and tumor microenvironment

“…cGMP generation was quantified by radioimmunoassay Notably, cellular invasion induced by PAR-1 activation in the presence of the sGC/cGMP activator BAY41 in normoxia was blocked by simultaneous addition of KT5823 (2 and 20 mM), as shown in Figure 8b. To further demonstrate the direct implication of the cGMP/ PKG cascade in the PAR-1 proinvasive activity, we confirmed that 8-Br-cGMP (5 mM) behaved as a selective PAR-1 commutator (Figure 8c): (1) this cell-permeant cGMP analog was ineffective in promoting the proinvasive activity of PAF and Met receptors (Kotelevets et al, 1998;De Wever et al, 2004) and (2) the invasive response determined by 8-Br-cGMP and PAR-1 activation was blocked by 15 min preincubation of HCT8/S11 cells with the PKG inhibitor (data not shown, n ¼ 3 experiments). Figure 6 Induction of PAR-1 proinvasive activity by hypoxia is mediated by the Gaq/PLCb/Ca-MLCK cascade and small GTPase Rac1.…”

“…The halfmaximal effect of insulin on collagen invasion was observed at the potency EC 50 of 0.6 nM consistent with activation of insulin receptors in intestinal epithelial cells. Alternatively, insulin may act through additional targets by modulating positively cGMP generation and PI3-kinase pathways (Emami and Perry, 1984;Begum et al, 2002) involved in cancer cell invasion (Kotelevets et al, 1998). Interestingly, PAR-1 commutation induced by DN-RhoA, ROK inhibition, and DN-ROK ( Figure 1a, b, and d) is not associated with significant changes in PAR-1 expression in HCT8/S11 cells incubated with TRAP and under control conditions (Figure 1a and b, top panels).…”

Opposing roles of netrin-1 and the dependence receptor DCC in cancer cell invasion, tumor growth and metastasis

“…As with parental HCT8/S11 cells, control vector transfected HCT8/S11-pcDNA3 cells were noninvasive and external addition of netrin or NECA simulated collagen type I invasion. The invasive phenotype exhibited by the HCT8/S11-netrin cells (Supplementary data 1) was reversed by the inhibitors of the Rho-ROK axis and PI3K (Kotelevets et al, 1998;Barbier et al, 2001;Nguyen et al, 2005). Conversely, restoration of wt-DCC in DCC-deficient HCT8/S11 cells obliterated the proinvasive activity of netrin-1, NECA and other proinvasive agents, including TGFa and trefoil factors.…”