Nitric Oxide-Scavenging, Anti-Migration Effects, and Glycosylation Changes after Hemin Treatment of Human Triple-Negative Breast Cancer Cells: A Mechanistic Study

Abstract

The enhanced expression of nitric oxide (•NO) synthase predicts triple-negative breast cancer outcome and its resistance to different therapeutics. Our earlier work demonstrated the efficiency of hemin to scavenge the intra- and extracellular •NO, proposing its potency as a therapeutic agent for inhibiting cancer cell migration. In continuation, the present work evaluates the effects of •NO on the migration of MDA-MB-231 cells and how hemin modulates the accompanied cellular behavior, focusing on the corresponding expression of cellular glycoproteins, migration-associated markers, and mitochondrial functions. We demonstrated for the first time that while •NO induced cell migration, hemin contradicted that by •NO-scavenging. This was in combination with modulation of the •NO-enhanced glycosylation patterns of cellular proteins with inhibition of the expression of specific proteins involved in the epithelial–mesenchymal transition. These effects were in conjunction with changes in the mitochondrial functions related to both •NO, hemin, and its nitrosylated product. Together, these results suggest that hemin can be employed as a potential anti-migrating agent targeting •NO-scavenging and regulating the expression of migration-associated proteins.

Hemin as a Molecular Probe for Nitric Oxide Detection in Physiological Solutions: Experimental and Theoretical Assessment

“…These amplified kinetics started to slow down then but without any decay within the recorded period. Of note, these results confirm our previously reported observations on the degradation of different DETA-NO concentrations and release of ● NO, measured electrochemically …”

“…Of note, these results confirm our previously reported observations on the degradation of different DETA-NO concentrations and release of • NO, measured electrochemically. 9 However, in the presence of hemin, a change in luminescence kinetics was observed, where the light yield was relatively higher, and an intensive increase in luminescence started once the reaction was initiated. Here H 2 O 2 and luminol were added to premixed hemin and DETA-NO for 10 min.…”

“…Nitric oxide ( ● NO) is a main gasotransmitter, responsible for the regulation of different biological activities, such as vasodilation, , blood pressure, neuromodulation, and inflammation . Moreover, ● NO plays multiple roles in the progression of different types of cancers. − Hence, different ● NO-releasing/generating compounds and materials have been used for modulating the levels of ● NO toward the treatment of different diseases as well as from basic research perspective. − Thus, tremendous efforts were made toward the detection of ● NO in solutions, which rely mainly on chemiluminescence (CL) − and amperometric detection. − However, from the literature, two main sensitive techniques have been majorly employed for the real-time detection of ● NO in solutions, and these mainly rely on electrochemical and ozone-based CL methods. , These two methods can detect minute concentrations of ● NO (in micromolar to picomolar) with a high resolution and tunable sensitivity and selectivity, particularly in the case of the amperometric detection of ● NO . Nonetheless, the foam produced because of nitrogen bubbling and the protein constituents within various culture media pose challenges to measurement sensitivity.…”

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer

“…These findings underscore the association of NOS2 with higher tumor grade, increased lymph node positive status, and enhanced tumor vascularity, suggesting NOS2’s role as a promoter of cancer progression [ 59 , 60 , 61 ]. Mechanistically, NO is implicated in increased proliferation, adhesion, and migration of tumor cells [ 62 ]. NO has also been shown to promote angiogenesis and regulate the activity of a variety of matrix proteins associated with cancer progression and drug resistance [ 63 ].…”