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Review
. 2013 Sep;13(8):1241-9.
doi: 10.2174/1566524011313080002.

iNOS: a potential therapeutic target for malignant glioma

A Jahani-Asl  1 , A Bonni
Affiliations
Review

iNOS: a potential therapeutic target for malignant glioma

A Jahani-Asl et al. Curr Mol Med. 2013 Sep.

Abstract

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.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors confirm that this article content has no conflicts of interest.

Figures

Fig. (1)
Fig. (1). Inhibitors of iNOS pathway may provide the basis for treatment of human glioblastoma tumors
(A). STAT3-iNOS signaling regulates EGFRvIII-mediated glial transformation. In EGFRvIII-expressing astrocytes, endogenous STAT3 occupies the promoter of the iNOS gene to regulate its transcription. STAT3 induces the expression of a reporter gene driven by the iNOS promoter, and mutation of a conserved STAT3 binding site within the iNOS promoter blocks the STAT3-induced expression of the reporter gene. The downstream signaling mechanisms by which iNOS regulates tumorigenesis remain to be studied. Here, we propose upregulation of cytokines such as IL8 and COX2, or changes in cell cycle kinetics as potential mechanism by which iNOS may regulate tumorigenesis. (B) Pharmacological inhibition of iNOS pathway or knockdown (KD) of iNOS by RNA interference (RNAi) suppresses tumor growth in vivo. The selective iNOS inhibitors 1400W and S-MIU and the NO scavenger c-PTIO reduce the population growth of EGFRvIII-expressing astrocytes. Knockdown of iNOS by RNA interference (Si-RNA) also reduces the population growth of these cells. iNOS knockdown EGFRvIII-expressing astrocytes fail to produce tumors or produce much smaller tumors than control EGFRvIII-expressing astrocytes. iNOS inhibition may therefore have potential therapeutic value in the treatment of glioblastoma.
Fig. (2)
Fig. (2). Future STAT3-based-patient-tailored therapies for malignant glioma
Following surgical excision of tumors, tumor cells can be dissociated and cultured. Cells can be enriched for tumor stem cells based on culture conditions. Brain tumor stem cells (BTSCs) can be genetically manipulated by lentiviral-based system. To identify STAT3 global networks, STAT3-KD-BTSCs and control counterparts can be subjected to chromatin immunoprecipitation with a STAT3 antibody followed by massive parallel sequencing (ChIP-Seq). To derive the functional relevance of those targets, BTSCs will be subjected to RNA-Seq and whole genome analyses. Identified targets will be assessed in functional experiments in animal models. An array of drugs and inhibitors can be assessed to identify the unique drug susceptibilities of a given tumor.
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