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


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 micromol/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.
Chiang
George J
GJ
Department of Urology, Lahey Clinic Medical Center, Burlington, MA 01805, USA.
Billmeyer
Brian R
BR
Canes
David
D
Stoffel
John
J
Moinzadeh
Alireza
A
Austin
Christina A
CA
Kosakowski
Monika
M
Rieger-Christ
Kimberly M
KM
Libertino
John A
JA
Summerhayes
Ian C
IC
D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051180:Desmoplakins; D006801:Humans; D007928:Lethal Dose 50; D009361:Neoplasm Invasiveness; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000494:pharmacology*; D015534:Trans-Activators / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology; D051176:beta Catenin; D051185:gamma Catenin
C412373:AG 1879; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; C502403:FAT1 protein, human; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D015534:Trans-Activators; D051176:beta Catenin; D051185:gamma Catenin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt