Abstract C19: Nelfinavir-induced autophagy and cell death as potential anticancer therapy for KSHV-associated lymphomas.

Abstract

Abstract Kaposi sarcoma associated herpes virus (KSHV) is implicated in primary effusion lymphoma (PEL) and several other malignancies. Following infection, the virus evades the immune system by maintaining its genome in a latent state and only expressing few viral genes. Activation of KSHV lytic replication in vitro leads to viral lytic gene expression, the production of infectious virus and cell death. We previously showed that activation of herpes virus lytic replication can be achieved by treating PEL tumor cells with the proteasome inhibitor, bortezomib which induces endoplasmic reticulum (ER) stress. Here, we investigate the effects of nelfinavir, a FDA approved human immunodeficiency virus (HIV) protease inhibitor with anti-cancer activity. Anti-cancer effects of nelfinavir range from the induction of ER stress and apoptosis to Akt inhibition. Treatment of PEL cell lines with nelfinavir resulted in increased expression of ER stress markers: ATF4, CHOP and spliced XBP-1. Additionally, we observed nelfinavir-induced autophagy and cell death as indicated by an increase in LC-3B processing and a decrease in cell viability. We also observed the formation of autophagosomes by electron microscopy. In KSHV-infected tumor cells treated with nelfinavir, ER stress and autophagy precedes viral lytic gene expression. However, we show that while nelfinavir activates lytic gene expression, it also inhibits the export and cell-to-cell spread of infectious herpes viruses. At clinically relevant concentrations, nelfinavir induces autophagy and cell death in PEL cells while inhibiting virus export making it an attractive candidate for virus-associated cancer therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C19. Citation Format: Nene Kalu, Sunetra Biswas, Courtney Shirley, Meir Shamay, Richard F. Ambinder. Nelfinavir-induced autophagy and cell death as potential anticancer therapy for KSHV-associated lymphomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C19.