The src‐family kinase inhibitor PP2 suppresses the in vitro invasive phenotype of bladder carcinoma cells via modulation of Akt

Abstract

OBJECTIVE To evaluate PP2 as a modulator of the cadherin/catenin complex in late‐stage bladder carcinoma cells, and to assess its potential invasion‐suppressor activity in this model. MATERIALS AND METHODS A panel of five human bladder carcinoma cells, characterizing late‐stage disease, was used to determine the concentration for 50% inhibition of PP2 in cell‐proliferation assays. Modulation of cadherin/catenin expression by PP2 was determined in Western blot analysis, with an assessment of the activation status of mitogen‐activated protein kinase and Akt signalling pathways. Altered invasive capacity linked to these variables was determined in standard in vitro invasion assays. RESULTS PP2 elicited concentration‐dependent growth inhibition in all bladder cell lines within the panel, with growth suppression recorded at 10–35 µmol/L PP2. Distinct morphological changes were recorded in cell lines exposed to PP2, accompanied by up‐regulation of plakoglobin expression in a subset of lines. Exposure of cells to PP2 resulted in inactivation of Akt in all cells and a concomitant reduction in in vitro invasive capacity. CONCLUSIONS These results show that PP2 inhibits bladder carcinoma cell growth and can modulate plakoglobin expression in a subset of cell lines. In addition, PP2 can suppress the in vitro invasive capacity of bladder carcinoma cells by modulating the activation status of Akt.

Hsp27 Inhibits Bax Activation and Apoptosis via a Phosphatidylinositol 3-Kinase-dependent Mechanism

“…Hsp27 expression also failed to slow the loss of phosphoserine 473 -Akt during stress (Fig. 6A), indicating that Hsp27 does not promotes Akt activation by regulating PP2, the phosphatase responsible for inactivating Akt (44). Alternatively, Hsp27 might directly regulate Akt activation.…”

Focal adhesion kinases crucially regulate TGFβ-induced migration and invasion of bladder cancer cells via Src kinase and E-cadherin

“…So, Src protein is one of the most important regulators in FAK-associated signal transduction. PP2 is an inhibitor of Src family tyrosine kinases and shows >10,000-fold selection over JAK2 and ZAP-70 41. PP2 is able to block Tyr416 phosphorylation of Src.…”

PI3K/Akt signalling is required for the attachment and spreading, and growth in vivo of metastatic scirrhous gastric carcinoma

“…This observation is consistent with our data, because p85 was not associated with paxillin in OCUM-2MD3 cells, indicating that spreading of cells modulated by PI3K through integrin signalling is dependent on vinculin, but not paxillin. Src kinase has many cellular functions such as growth factor-induced proliferation, invasion, and protection from apoptosis (Brown and Cooper, 1996; Chiang et al , 2005). In OCUM-2MD3 cells, constitutive activation of Src may cause usual interaction of PI3K, and these activations and associations may be both necessary for cell adhesion to ECM, but Src contribution may be partial in OCUM-2MD3 cell adhesion, because specific Src inhibitor, PP2, significantly inhibited the adhesion of OCUM-2MD3 cells to type IV collagen, but less compared with PI3K inhibitor (Supplementary Figure 3B).…”