NO and hepatocellular cancer

Abstract

NO has broad and sometimes dichotomous roles in cancer. The effects of NO in tumours depend on the type and localization of NOS isoforms, concentration and duration of NO exposure, and cellular sensitivity to NO. Hepatocellular carcinoma (HCC) is a common and lethal disease for which no effective therapy other than surgical resection exists. Over two decades of research has yielded evidence that NO generated by the inducible NOS (iNOS or NOS2) contributes to HCC progression in at least a subset of patients with HCC. The co-expression of iNOS with COX-2 may portend a particularly aggressive cancer phenotype in HCC and at the same time reveal an opportunity for pharmacological intervention. In this review, we focus on what is known about the influence of NO in HCC neoplastic transformation, proliferation and apoptosis, angiogenesis, invasion, and metastasis, cancer stem cells, and the host immune response against the tumour. We discuss the implications of recent findings for targeting the NO pathways in HCC.

FIGURE 1

In liver cancer stem cells, to synthesize NO, all isoforms of NOS (nNOS/NOS1, iNOS/NOS2, and eNOS/NOS3) utilize l‐arginine as substrate and depend on the cofactors/coenzymes NADPH and oxygen (O₂) to oxidize a guanido nitrogen of arginine to NO with citrulline and NADP as co‐product. NO‐induced Notch activation in LCSC involved cGMP‐dependent ADAM17 activation and the cleavage of membrane Notch. NICD then enters the nucleus, activates transcription of target genes, and promotes the self‐renewal capacity, tumorgenicity, and chemotherapy resistance. Potential strategies to suppress NO availability in clinic trials include removal of the NO substrate arginine (arginine deiminase), administration of non‐selective NOS inhibitors (L‐NMMA/NMA), or the use of selective iNOS inhibitor (ASP9853, SC‐51, SMT, and SD‐6010)