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KSHV-induced notch components render endothelial and mural cell characteristics and cell survival
Ren Liu1, Xiuqing Li, Anil Tulpule
1Departments of Medicine, University of Southern California, Los Angeles, USA.
Blood
|December 8, 2009
Summary
Kaposi sarcoma-associated herpesvirus (KSHV) hijacks Notch signaling to promote Kaposi sarcoma (KS) development. Targeting this pathway with soluble Dll4 shows promise for KS treatment.
Area of Science:
- Oncology
- Virology
- Cell Biology
Background:
- Kaposi sarcoma-associated herpesvirus (KSHV) is crucial for Kaposi sarcoma (KS) development.
- Notch signaling is implicated in KS cell survival and KSHV lytic replication.
Purpose of the Study:
- To investigate the regulatory role of KSHV in Notch signaling components.
- To evaluate the therapeutic potential of targeting the Notch pathway in KSHV-driven cancers.
Main Methods:
- Analysis of Notch receptor and ligand expression in KSHV-infected lymphatic endothelial cells.
- Assessment of KSHV viral proteins' effect on Notch pathway components and cell markers.
- In vitro and in vivo evaluation of gamma-secretase inhibitor and soluble Dll4 efficacy against KSHV-transformed cells and KS xenografts.
Main Results:
- KSHV infection induces Notch3, Notch4 receptors, Dll4, Jagged1 ligands, and activates Notch signaling in endothelial cells.
- KSHV proteins upregulate Notch receptors, ligands, downstream targets, and CD133, promoting cell dedifferentiation/trans-differentiation.
- Soluble Dll4 effectively inhibited KSHV-transformed cell growth, induced cell death, and reduced tumor perfusion in vivo.
Conclusions:
- KSHV directly regulates Notch signaling components, contributing to KS pathogenesis.
- Targeting the Notch pathway, particularly with soluble Dll4, represents a viable therapeutic strategy for Kaposi sarcoma.
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