Latent KSHV Infected Endothelial Cells Are Glutamine Addicted and Require Glutaminolysis for Survival (PLoS Pathog 11:e1005052, 2015)

報告日期: 2015/10/27
報告時間: 4:00/4:50
報告學生: 廖聰羽
講評老師: 楊孔嘉
附件下載: 下載[1508-1443054226-1.pdf] 

Latent KSHV Infected Endothelial Cells Are Glutamine Addicted and Require Glutaminolysis for Survival

Erica L. Sanchez, Patrick A. Carroll, Angel B. Thalhofer, Michael Lagunoff

 PLoS Pathog, 2015. 7(1): p. e1005052.

Speaker:廖聰羽                                        Date:2015/10/27

Commentator:楊孔嘉博士                                Room : 602

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma, a highly vascularized tumor comprised predominantly of spindle cells of endothelial origin. Since tumor cells often show altered metabolic pathways for some unique strategies of growth, survival, and malignant progression, the authors speculated that KSHV may also affect cell metabolism in a tumor-like fashion. Proving the speculation, they previously found that glycolysis and lipogenesis pathways are upregulated in KSHV-infected endothelial cells, and blockage of either pathway can induce apoptosis of the infected cells but not uninfected cells. In this study, the authors provided additional evidence showing that KSHV can affect glutamine metabolism. First, latent KSHV infection in endothelial cells resulted in increase of exogenous glutamine uptake, and depletion of glutamine preferentially induced caspase-dependent apoptosis of virus-infected endothelial cells. The KSHV-induced glutamine addiction was attributed to the requirement for glutaminolysis to replenish the tri-carboxylic acid cycle, as supplementation of α-ketoglutarate or pyruvate promoted survival of the glutamine-deprived cells. Upon KSHV infection, expression of a glutamine transporter SLC1A5 and its upstream transcription factors c-Myc/Max/MondoA/Mlx was upregulated. Similar to glutamine deprivation, treatment with a SLC1A5 inhibitor or knockdown of MondoA caused death of KSHV-infected endothelial cells, which was also prevented by α-ketoglutarate supplementation. Therefore, KSHV may activate the Myc/MondoA network to enhance SLC1A5 expression, glutamine uptake, glutaminolysis, and addiction to glutamine for cell survival. Drugs targeted to glutamine metabolism may be of therapeutic value to preferentially kill KSHV-infected endothelial cells.

References:

Delgado T, Sanchez EL, Camarda R, Lagunoff M. Global metabolic profiling of infection by an oncogenic virus: KSHV induces and requires lipogenesis for survival of latent infection. PLoS pathogens. 2012; 8(8):e1002866–e.