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Role of protein kinase C β and vascular endothelial growth factor receptor in malignant pleural mesothelioma: Therapeutic implications and the usefulness of Caenorhabditis elegans model organism. | LitMetric

AI Article Synopsis

  • The study investigates the roles of protein kinase C (PKC)-β and vascular endothelial growth factor receptor (VEGFR)-2 in malignant pleural mesothelioma (MPM) using specific inhibitors, enzastaurin and KRN633.
  • Results showed that both PKC-β and VEGFR-2 are overexpressed in MPM cells, and enzastaurin significantly decreased cell viability and affected multiple signaling pathways, while KRN633 had a lesser effect.
  • Enzastaurin's potency was demonstrated through its ability to induce phenotypic changes in the nematode C. elegans, suggesting its potential as a screening tool for new kinase inhibitors.

Article Abstract

Purpose: To examine the role of both protein kinase C (PKC)-β and vascular endothelial growth factor receptor (VEGFR)-2 in malignant pleural mesothelioma (MPM) using respective inhibitors, enzastaurin and KRN633.

Materials And Methods: MPM cell lines, control cells, and a variety of archived MPM tumor samples were used to determine the protein expression levels of PKC-β, VEGFR-2, VEGF, and p-AKT. Effects of enzastaurin and KRN633 on phosphorylation status of key signaling molecules and viability of the mesothelioma cells were determined. The common soil nematode, Caenorhabditis elegans, was treated with enzastaurin to determine its suitability to screen for highly potent kinase inhibitors.

Results: PKC-β1, PKC-β2 and VEGFR-2/KDR were overexpressed in MPM cell lines and MPM tumor tissues. Enzastaurin treatment resulted in significant loss in viability of VEGF induced cell proliferation; however, the effect of KRN633 was much less. Enzastaurin also dramatically decreased the phosphorylation of PKC-β, its downstream target p-AKT, and surprisingly, the upstream VEGFR-2. The combination of the two drugs at best was additive and similar results were obtained with respect to cell viability. Treatment of C. elegans with enzastaurin resulted in clear phenotypic changes and the worms were hypermotile with abnormal pattern and shape of eggs, suggesting altered fecundity.

Conclusions: PKC-β1 and VEGFR-2 are both excellent therapeutic targets in MPM. Enzastaurin was better at killing MPM cells than KRN633 and the combination lacked synergy. In addition, we show here that C. elegans can be used to screen for the next generation inhibitors as treatment with enzastaurin resulted in clear phenotypic changes that could be assayed.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3049271PMC
http://dx.doi.org/10.4103/1477-3163.77274DOI Listing

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