Extracellular Hsp90 serves as a co-factor for NF-κB activation and cellular pathogenesis induced by an oncogenic herpesvirus

[摘要] The Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS)—the most common tumor associated with HIV infection and an important cause of morbidity and mortality in this patient population. The majority of patients with KS exhibit little or no clinical response to existing therapies. The nuclear factor-kappaB (NF-κB) family of transcription factors plays a critical role in facilitating cancer pathogenesis associated with oncogenic viruses, and a better understanding of how cellular factors regulate NF-κB activation in the context of KSHV infection may facilitate development of new therapies for KS. Existing data implicate heat shock protein-90 associated with the cell surface (csHsp90) as a co-factor in cancer cell migration and invasion, and we recently reported that csHsp90 serves as a co-factor for mitogen-activated protein kinase (MAPK) activation during de novo KSHV infection. However, whether csHsp90 regulates NF-κB activation, or cellular pathogenesis associated with KS, has not been established. We have found that csHsp90 serves as an important co-factor for canonical NF-κB activation by KSHV during de novo infection of primary human cells relevant to KS. Furthermore, our correlative functional studies reveal that csHsp90 inhibition suppresses KSHV-induced, NF-κB-dependent secretion of the pro-migratory factors interleukin-8 and vascular endothelial growth factor as well as invasiveness for primary cells following de novo infection. These data implicate csHsp90 in KSHV-mediated activation of NF-κB and associated pathogenesis, and support the potential utility of targeting csHsp90 as a therapeutic approach for KS.

[学科分类] 肿瘤学

[关键词] Cancer;Kaposi's sarcoma;NF-κB;KSHV;heat shock protein;invasion;transcription factors;signal;trans-duction