Abstract
Background: This study aimed to evaluate the impact of selective abrogation of either the MEK/ERK1/2 (UO126 or PD98059) or the PI3K/AKT (LY294002) signaling cascade on cell proliferation, motility and invasion and production of VEGF (collectively termed pro-metastasis phenotypes) in cultured malignant pleural mesothelioma (MPM) cells. Materials and Methods: Treatment-induced cytotoxicity was evaluated by MTT or Annexin V assays. Cell motility was assessed by wound healing and Matrigel invasion assays. VEGF in conditioned media of cancer cells was measured by ELISA. Results: LY294002 and UO126 significantly inhibited cell proliferation and clonogenicity of MPM cells in vitro. A substantial reduction of cell motility, Matrigel invasion as well as inhibition of basal or EGF-induced VEGF production were observed in drug-treated cells. Conclusion: The selective MEK or PI3K kinase inhibitors are equally effective in down-regulating the expression of pro-metastasis phenotypes, suggesting that MEK or PI3K are appropriate targets for the development of molecular therapeutics for malignant pleural mesothelioma.
- EGFR
- MAPK
- MEK
- ERK1/2
- PI3K inhibitor LY294002
- MEK inhibitor UO126
- apoptosis
- angiogenesis
- prometastasis phenotypes
- motility
Footnotes
-
↵* The authors contributed equally to this work.
-
↵** National Institutes of Health - Clinical Research Training Program, Bethesda, MD, U.S.A.
-
Abbreviations: EGFR, epidermal growth factor receptor; MPM, malignant pleural mesothelioma; MTT, 4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; MEK, MAPK/ERK kinase; PI3K, phosphatidylinositide 3-kinase; PDK, 3-phosphoinositide-dependent kinase; VEGF, vascular endothelial cell growth factor; JAK/STAT, Janus kinase/signal transducers and activators of transcription; PLC, phospholipase C; PDGFR, platelet-derived growth factor; HGF, hepatocyte growth factor; IGFR, insulin growth factor receptor.
- Received January 12, 2006.
- Accepted January 24, 2006.
- Copyright© 2006 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved