Hsp90 Inhibitors Are Efficacious against Kaposi Sarcoma by Enhancing the Degradation of the Essential Viral Gene LANA, of the Viral Co-Receptor EphA2 as well as Other Client Proteins
Kaposi sarcoma (KS) is an angioproliferative tumor derived from endothelial cells in which tumor cells form aberrant vascular structures. Ephrin B2 and ephrin B4 (EphB4) are artery- and vein-specific proteins, respectively, with critical roles in vessel maturation. We investigated whether the disorganized KS vasculature was due to unbalanced expression of ephrin B2 and EphB4. Secondly, we wished to determine if human herpesvirus type 8 (HHV-8), the viral agent associated with KS, regulates ephrin B2 and EphB4. An arterial phenotype was observed in KS tissue and cell lines, as shown by abundant expression of ephrin B2 with little or no EphB4. Infection of venous endothelial cells with HHV-8 resulted in a phenotype switch from EphB4 to ephrin B2, similar to that seen with vascular endothelial growth factor (VEGF). The HHV-8 effect on ephrin B2 expression was reproduced with the HHV-8-specific viral G-protein-coupled receptor. We also showed that ephrin B2 expression is required for KS cell viability by knock down with siRNA. KS is the first example of a human tumor with a predominantly arterial phenotype. This predominance can be attributed to expression of HHV-8 proteins and their downstream effects. Ephrin B2 is thus an important novel factor in KS biology and a potential target for therapy.