Angiogenin (ANG) is a 14-kDa multifunctional proangiogenic secreted
protein whose expression level correlates with the aggressiveness of several
tumors. We observed increased ANG expression and secretion in endothelial cells during de novo
infection with Kaposi's sarcoma-associated herpesvirus (KSHV), in cells expressing only
latency-associated nuclear antigen 1 (LANA-1)
protein, and in KSHV latently infected
primary effusion lymphoma (PEL) BCBL-1 and BC-3 cells. Inhibition of
phospholipase Cγ (PLCγ) mediated ANG's nuclear translocation by
neomycin, an
aminoglycoside antibiotic (not G418-neomicin), resulted in reduced KSHV latent gene expression, increased lytic gene expression, and increased cell death of KSHV(+) PEL and endothelial cells. ANG detection in significant levels in KS and PEL lesions highlights its importance in KSHV pathogenesis. To assess the in vivo antitumor activity of
neomycin and
neamine (a nontoxic derivative of
neomycin), BCBL-1 cells were injected intraperitoneally into NOD/SCID mice. We observed significant extended survival of mice treated with
neomycin or
neamine. Markers of
lymphoma establishment, such as increases in animal
body weight, spleen size,
tumor cell spleen infiltration, and
ascites volume, were observed in nontreated animals and were significantly diminished by
neomycin or
neamine treatments. A significant decrease in LANA-1 expression, an increase in lytic gene expression, and an increase in cleaved
caspase-3 were also observed in
neomycin- or
neamine-treated animal ascitic cells. These studies demonstrated that ANG played an essential role in KSHV latency maintenance and BCBL-1 cell survival in vivo, and targeting ANG function by
neomycin/
neamine to induce the apoptosis of cells latently infected with KSHV is an attractive therapeutic strategy against KSHV-associated
malignancies.