EFFECT OF DOSE AND DURATION OF DPTA NONOate TREATMENT ON HUMAN LUNG CANCER STEM CELL PHENOTYPE INDUCTION

Abstract

Tremendous advances have been made in the treatment of cancers during the past decades, but 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. This research showed how nitric oxide (NO), a key cellular modulator whose level is elevated in many tumors, affect 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. These effects of NO on stemness were reversible after cessation of the NO treatment for 7 days. Furthermore, such effect was reproducible using another NO-donor, SNAP. Importantly, inhibition of NO by the known NO scavenger PTIO strongly inhibited cellular CSC-like phenotype. Lastly, this research unveiled the underlying mechanism of NO action through the activation of caveolin-1 (Cav-1), which is up regulated by NO and is responsible for the aggressive behavior of the cells. These findings indicate a novel role of NO in CSC regulation and its importance in aggressive cancer behaviors through Cav-1 up regulation.