(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have discovered how
the Kaposi’s sarcoma-associated herpesvirus (KSHV) subverts
a normal cell process in order to promote tumor growth. The finding,
published in the most recent issue of PLoS Pathogens, offers
new potential strategies for treating Kaposi’s sarcoma and
other cancers associated with viruses.
KSHV is an opportunistic pathogen that rarely affects individuals
with normal immune systems. However, HIV/AIDS patients and those
who are immune suppressed such as organ transplant patients are
at high risk for developing Kaposi’s sarcoma and another cancer
called primary effusion lymphoma.
The study describes how a KSHV-encoded protein, called latency-associated
nuclear antigen, or LANA, tricks the cell into destroying two major
suppressors of tumor growth called von Hippel Lindau (VHL) and p53.
“In addition, we have shown that when LANA expression was
blocked, the tumor suppressors again become stable suggesting a
direct role of the viral protein in regulation of these major cell
proteins,” says lead author Erle Robertson, PhD,
Professor of Microbiology and the Director of Tumor Virology at
Penn’s Abramson Cancer Center.
The trick is played out in a cell process called ubiquitylation.
This refers to a pathway in all cells whereby a protein aptly named
ubiquitin binds to cellular proteins and marks them for degradation.
This process can be likened to putting out the garbage for disposal.
Ubiquitylation and degradation involve a complex set of proteins
in addition to ubiquitin. “We found that the viral LANA has
an amino acid motif that mimics non-viral cell proteins usually
involved in the ubiquitylation process,” says Robertson. This
motif, or stretch of amino acids, normally enables LANA to bind
to tumor suppressors p53 or VHL, thus bringing them into the active
ubiquitylation complex. Once in the complex, the tumor suppressors
are targeted for degradation.
Tumor suppressors, as their name implies, prevent or limit the
growth of tumors in numerous ways. One way the tumor suppressors
p53 and VHL work is to mark a key protein that controls the blood
supply in a tumor mass. Once marked, this protein called hypoxia-induced
factor 1a (HIF-1a) is degraded through ubiquitylation before it
can start the process of activating genes responsible for inducing
growth of more blood vessels to supply the tumor with oxygen. However,
in a KSHV-infected cell, p53 and VHL themselves would be targeted
for degradation and HIF-1a would then be free to activate genes
involved in growth of blood vessels to increase the blood supply
to the tumor.
“Use of such proteosome inhibitors as Bortezomib as cancer
therapeutic agents has been ongoing for the last four to five years
and this study provides crucial step in understanding the mechanism
for anti-tumorigenic activity against KSHV-associated human cancers,”
concludes Robertson. “Additionally, we can now use compounds
known to inhibit proteosome activity to determine their effectiveness
in inhibiting the Kaposi’s viral-induced degradation of these
two major tumor suppressors.” This, he says, is important
in finding or designing drugs that can be specifically used against
KSHV, and potentially, other virus-associated cancers.
This work was funded by the National Institutes of Health and the
Leukemia and Lymphoma Society. Co-authors in addition to Robertson
are Qi-Liang Cai, Jason S. Knight, Suhbash C. Verma, and Philip
Zald, all from Penn.
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