Avril V. Somlyo, PhD

Avril V. Somlyo, PhD

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Rho signaling pathway (Prostate cancer, Gliomas, Angiogenesis)

The focus of the Somlyo laboratory is the study of signaling molecules that regulate contractility of smooth muscle as well as the myosin II based migration of non-muscle cells such as occurs in metastatic processes and angiogenesis.  Smooth muscle and non-muscle myosin II is activated by phosphorylation of the regulatory light chains by myosin light chain kinase (MLCK) and inactivated by dephosphorylation through myosin light chain phosphatase (MLCP).  They study the RhoA/Rho-kinase pathway, which when activated inhibits MLCP leading to an increase in contractility or cell migration.  They have demonstrated that MLCP is present in prostate cancer cells and in endothelial cells and have found that the Rho-kinase inhibitor, Y-27632, inhibits in vitro chemotactic migration of highly invasive human prostate cancer (pC3) cells and metastatic tumor growth in immune-compromised mice.  Y-27632 also reduced myosin light chain phosphorylation and inhibited angiogenesis in in vitro assays.   The number and size of tumors following intracardiac injection into 30-immune-incompetent mice was markedly reduced during, and for a period after treatment of the 15 mice that received Y-27632 administered through Alzet osmotic pumps implanted interperitoneally. Survival of treated animals was also significantly prolonged.

In preliminary experiments Rho-kinase inhibitor was tested for its ability to impede the migration of U-87 human glioma cells injected into the right corpus striatum with the help of a Kopf stereotactic frame with tumor volume estimated by MRI at two weeks following injection.  Preliminary data from 46 mice who received either all, none, or varying combinations of Rho-kinase inhibitor, Marimastat and paclitaxel showed that the Rho-kinase inhibitor reduced tumor volume at two weeks (p < 0.0001) while both Marimastat and paclitaxel showed no effect on tumor volume.  At the cellular level Rho-kinase inhibitor decreased phosphorylation of MYPT-1 in U-87 cells suggesting that the reduction of cell migration could reflect the enhanced myosin phosphatase activity and decreased contractility of these cells.