title: Effect of an epidermal growth factor receptor tyrosine kinase inhibitor on actin remodeling in an in vitro bladder cancer carcinogenesis model.
abstract: Alteration of actin remodeling is a marker of malignant-associated field defect and a potential surrogate biomarker for chemoprevention trials. We tested erlotinib, a specific tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), on actin remodeling in a bladder carcinogenic model consisting of untransformed HUC-PC cells and transformed MC-T11 cells, both derived from the same normal human urothelial clone immortalized by SV40. Erlotinib had a selective growth inhibitory and actin remodeling effect on MC-T11 cells over HUC-PC cells, as examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and immunofluorescence labeling with laser scan cytometer analysis, respectively. The IC(50) of untransformed HUC-PC cells was significantly higher than that of transformed MC-T11 cells (P < 0.05, t test). The actin remodeling effect was more prominent at lower dosage levels (1/8-1/4 of IC(50)), which was accompanied by an increased cell adhesion and decreased motility. At higher dosage levels (1/2 of IC(50)), erlotinib induced a decreased adhesion and anoikis (detachment-associated apoptosis). The transformed MC-T11, but not HUC-PC, showed a weak constitutive EGFR phosphorylation activity, which was inhibited by erlotinib in a dose-response manner. However, on epidermal growth factor stimulation, both cell lines showed a similar dose-response inhibitory effect on phosphorylated EGFR and mitogen-activated protein kinase (MAPK; P44/P42) activities, and MAPK inhibitor PD98059 showed no specific effect on erlotinib-induced actin remodeling, suggesting that pathways other than MAPK (P44/P42) may be responsible for erlotinib-induced actin remodeling. The findings provide evidence to support erlotinib-based bladder cancer chemoprevention and using actin remodeling as a marker for erlotinib-based intervention trials.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Box 951732, Los Angeles, CA 90095-1732, USA.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Jin
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Iwata
authors.forename: Arie
authors.initials: A
authors.lastname: Belldegrun
authors.forename: Robert
authors.initials: R
authors.lastname: Figlin
authors.forename: Allan
authors.initials: A
authors.lastname: Pantuck
authors.forename: Zuo-Feng
authors.initials: ZF
authors.lastname: Zhang
authors.forename: Ronald
authors.initials: R
authors.lastname: Lieberman
authors.forename: Jianyu
authors.initials: J
authors.lastname: Rao
mesh_terms: D000199:Actins / Q000187:drug effects* / Q000378:metabolism; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000517:prevention & control
chemical_list: D000199:Actins; D016588:Anticarcinogenic Agents; D005419:Flavonoids; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one