Effect of an epidermal growth factor receptor tyrosine kinase inhibitor on actin remodeling in anin vitrobladder cancer carcinogenesis model

Abstract

Alteration of actin remodeling is a marker of malignantassociated 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 (detachmentassociated apoptosis). The transformed MC-T11, but not HUC-PC, showed a weak constitutive EGFR phosphorylation activity, which was inhibited by erlotinib in a doseresponse manner. However, on epidermal growth factor stimulation, both cell lines showed a similar dose-response inhibitory effect on phosphorylated EGFR and mitogenactivated 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.

KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)

“…3 C). Consistent with published results 27 the estimated IC 50 value is in the order of 5 µmol/L. Thus, erlotinib inhibits migration more efficiently than it prevents an increase of the cell number.…”

Torilis japonica extract, a new potential EMT suppressor agent by regulation of EGFR signaling pathways

“…Previous research has focused on an anti-metastasis effect from one of these pathways, but not from both. As a consequence, while it was possible to discover the reduction in EMT from one of the EGFR downstream signaling pathways, the effect of the other pathway was unclear (33)(34)(35); on the other hand, in this study we found that TJE treatment led to a decrease in EGF-induced EMT though blocking of both pathways. TJE had a similar effect to the use of the inhibitors PD 98059 for Erk inhibition and LY 294002 for Akt inhibition (Fig.…”

Cell-Vision Fusion: A Swin Transformer-based Approach to Predicting Kinase Inhibitor Mechanism of Action from Cell Painting Data

“…The EGFR is an actin-binding protein 54 which has been shown to reorganize the junctional actin cytoskeleton 55 . PI3K can also disrupt the actin cytoskeleton 56 , while both contribute to actin filament remodelling throughout the cell 57,58 . EGFR is also highly connected to the functioning of the Golgi apparatus in protein transport 59,60 and is a plasma membrane receptor.…”