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

Posted by Article Type, Issue, Original Article, Vol 10, Issue 1Posted on

Sivakumar Loganathan1, Rajani Kanteti1, Shahid S Siddiqui2, Essam El-Hashani1, Maria Tretiakova3, Hari Vigneswaran1, Gustavo Cervantes1, Viswanathan Natarajan2, Aliya N Husain3, Everett E Vokes1, Hedy L Kindler1, Ravi Salgia1
1Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA
2Section of Pulmonary Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA
3Department of Pathology, University of Chicago, Chicago, IL 60637, USA
DOI: 10.4103/1477-3163.77274

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.

Keywords: Enzastaurin, KRN633, malignant pleural mesothelioma, PKC-β, VEGFR-2