Glioblastoma is the most aggressive adult
primary brain tumor. Although progress has been made in understanding the molecular mechanisms underlying these
tumors, current treatments are ineffective. Recent studies have identified iNOS as a critical regulator of glial transformation downstream of
EGFRvIII/STAT3 signaling, a key oncogenic pathway in
glioblastoma. STAT3 directly binds the promoter of the iNOS gene and thereby stimulates its expression. Importantly, inhibition of iNOS by genetic and pharmacological approaches impedes glial cell proliferation, invasiveness, and
tumor growth in vivo. iNOS expression is also elevated in a population of human
brain tumor stem cells (BTSCs), and iNOS is required for BTSC proliferation and
tumorigenesis. Together, these findings suggest that development of iNOS-targeted
therapies may prove valuable in the treatment of
glioblastoma. Here, we review our current understanding of iNOS signaling in the regulation of
glioblastoma pathogenesis and the potential mechanisms by which iNOS inhibition might suppress the malignant behavior of these devastating
tumors.