Sphingosine kinase-2 maintains viral latency and survival for KSHV-infected endothelial cells.

[primary effusion lymphoma]

Phosphorylation of sphingosine by sphingosine kinases (SphK 1 and SphK 2 ) generates sphingosine-1 -phosphate (S 1 P ), a bioactive sphingolipid which promotes cancer cell survival and tumor progression in vivo . We have recently reported that targeting SphK 2 induces apoptosis for human primary effusion lymphoma (PEL ) cell lines infected by the Kaposi 's sarcoma -associated herpesvirus (KSHV ), and this occurs in part through inhibition of canonical NF-κB activation . In contrast , pharmacologic inhibition of SphK 2 has minimal impact for uninfected B-cell lines or circulating human B cells from healthy donors . Therefore , we designed additional studies employing primary human endothelial cells to explore mechanisms responsible for the selective death observed for KSHV-infected cells during SphK 2 targeting . Using RNA interference and a clinically relevant pharmacologic approach , we have found that targeting SphK 2 induces apoptosis selectively for KSHV-infected endothelial cells through induction of viral lytic gene expression . Moreover , this effect occurs through repression of KSHV-microRNAs regulating viral latency and signal transduction , including miR-K 12 -1 which targets IκB α to facilitate activation of NF-κB , and ectopic expression of miR-K 12 -1 restores NF-κB activation and viability for KSHV-infected endothelial cells during SphK 2 inhibition . These data illuminate a novel survival mechanism and potential therapeutic target for KSHV-infected endothelial cells : SphK 2 -associated maintenance of viral latency .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated