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Adhesion of tumor cells onto the extracellular matrix (ECM) plays an important role in cancer metastasis. Cells are in dynamic contact with the ECM via integrin receptors, and both the integrin activity and the level of integrin expression are known to be influenced by various stimuli. It is known that both ionizing radiation (IR) and reactive oxygen species (ROS) can alter the adhesive affinity between tumor cells and extracellular matrix (ECM) proteins and that IR induces production of ROS. Therefore we evaluated the effect of ROS scavenger, N-acetyl-L-cysteine (NAC), on the adhesive affinity between MDA-MB-231 breast cancer cells and extracellular matrix (ECM) proteins after IR. We focused mainly on fibronectin, a representative ECM protein. Our data indicated that IR (20 Gy) significantly induced the breast cancer and lung cancer cell adhesion onto fibronectin at 24 hr post-irradiation. Our results using static cell adhesion assays indicated that continuously treating the breast cancer cells with LNAC (10 mM) for 24 h, starting immediately after IR (20 Gy), could inhibit IR-induced cell adhesion to ECM proteins at 24 h post-IR. This inhibition was correlated with a down-regulation of IR-induced surface expression of activated integrin beta 1, ROS elevation and vimentin expression, which is an epithelial-mesenchymal transition marker (EMT). Interestingly, when the cells were pretreated for 1 h, the inhibitory effects of LNAC were found to be either reduced or completely abrogated following 24 h or 2 h treatments, respectively. Our results demonstrated that the time and duration of LNAC treatment is critical for regulating IR-induced adhesive affinity, and thus metastatic potential, as well as the EMT process of breast cancer cells.Studies show that in addition to ROS, nitric oxide (NO) plays a role in regulating cancer cell adhesion and migration onto ECM. A new class of nitric oxide (NO)-releasing NSAIDs possessing a N-diazen-1-ium-1,2-diolate moiety (NONO-NSAIDs) were recently developed and have been shown to have less harmful side-effects in comparison with normal NSAIDs .In addition to their anti-inflammatory profile, NONO-NSAIDs have shown potential for usage in cancer prevention and treatment. However, the effects of NONO-NSAIDs on metastatic potential, or more specifically, cancer cell adhesion and migration, remain unexplored. In this study, we demonstrated that both NONO-naproxen and NONO-aspirin can reduce melanoma adhesion to VLA-4 ligands - VCAM-1 or fibronectin under fluid flow conditions or static conditions respectively. The NONOate moiety on the NSAIDs is critical for their function in reducing the avidity of melanoma cells. These findings led us to hypothesize that NONO-NSAIDs could potentially be a new class of anti-metastasis drugs for cancer treatment. |
