Am J Physiol Cell Physiol. 2014 Nov 19:ajpcell.00187.2014. doi: 10.1152/ajpcell.00187.2014. [Epub ahead of print]

Nitric Oxide induces Cancer Stem Cell-like Phenotypes in Human Lung Cancer Cells.

Yongsanguanchai N¹, Pongrakhananon V¹, Mutirangura A¹, Rojanasakul Y², Chanvorachote P³.

Abstract

Even though tremendous advances have been made in the treatment of cancers during the past decades, success rate among cancer patients is still dismal largely due to problems associated with chemo/radio-resistance and relapse. Emerging evidence has indicated that cancer stem cells(CSCs) are behind the resistance and recurrence problems, but our understanding of their regulation is limited. Rapid reversible changes of CSC-like cells within tumors may result from the effect of biological mediators found in tumor microenvironment. Here we show how nitric oxide (NO), a key cellular modulator whose level is elevated in many tumors, affects CSC-like phenotypes of human non-small-cell lung carcinoma (NSCLC) H292 and H460 cells. Exposure of NO gradually altered the cell morphology towards mesenchymal stem-like shape. NO exposure promoted CSC-like phenotype indicated by increased expression of known CSC markers, CD133 and ALDH1A1, in the exposed cells. This effect of NO on stemness was reversible after cessation of the NO treatment for 7 days. Furthermore, such effect was reproducible using another NO-donor, S-nitroso-N-acetylpenicillamine (SNAP). Importantly, inhibition of NO by known NO scavenger 2-(4-carboxy-phenyl)-4,4,5,5 tetramethylimidazoline-1-oxy-3-oxide (PTIO) strongly inhibited CSC-like aggressive cellular behavior and marker expression. Lastly, we unveiled the underlying mechanism of NO action through the activation of caveolin-1 (Cav-1) which is upregulated by NO and is responsible for the aggressive behavior of the cells, including anoikis resistance, anchorage-independent cell growth, and increased cell migration and invasion. These findings indicate a novel role of NO in CSC regulation and its importance in aggressive cancer behaviors through Cav-1 upregulation.