Gene expression profiles of NO- and HNO-donor treated breast cancer cells: insights into tumor response and resistance pathways

Abstract

Nitric oxide (NO) synthase 2 (NOS2), a major inflammatory protein, modulates disease progression via NO in a number of pathologies, including cancer. The role of NOS2-derived NO is not only flux-dependent, which is higher in mouse vs. human cells, but also varies based on spatial and temporal distribution both within tumor cells and in the tumor microenvironment. NO donors have been utilized to mimic NO flux conditions and to investigate the effects of varied NO concentrations. As a wide range of effects mediated by NO and other nitrogen oxides such as nitroxyl (HNO) have been elucidated, multiple NO- and HNO-releasing compounds have been developed as potential therapeutics, including as tumor modulators. One of the challenges is to determine differences in biomarker expression from extracellular vs. intracellular generation of NO or HNO. Taking advantage of new NO and HNO releasing agents, we have characterized the gene expression profile of estrogen receptor-negative human breast cancer (MDA-MB-231) cells following exposure to aspirin, the NO donor DEA/NO, the HNO donor IPA/NO and their intracellularly-activated prodrug conjugates DEA/NO-aspirin and IPA/NO-aspirin. Comparison of the gene expression profiles demonstrated that several genes were uniquely expressed with respect to NO or HNO, such as miR-21, HSP70, cystathionine γ-lyase and IL24. These findings provide insight into targets and pathways that could be therapeutically exploited by the redox related species NO and HNO.

Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

“…Although iNOS expression was negatively correlated with lesion grade in a cohort of invasive ductal breast carcinomas, 39 indicating a possible role of iNOS in the prevention of metastasis, iNOS expression has conversely been implicated as a marker of poor prognosis in several malignancies, including prostate, colon, and breast 40 . Stratification of a breast cancer patient cohort by estrogen receptor (ER) expression revealed that iNOS expression was predictive of poorer survival in ER − patients, 41 whereas high iNOS expression was similarly detrimental in a range of triple-negative breast cancer patient cohorts 42 .…”

Nifedipine stimulates proliferation and migration of different breast cancer cells by distinct pathways

“…A previous study (26) revealed that eNOS and weak iNOS were expressed in MCF-7 cells and served an important role in cell proliferation. In general, NO can stimulate the proliferation and migration of epithelial cells in addition to gene profile expression (27).…”

Nitroxyl as a Potential Theranostic in the Cancer Arena

“…In this study, Norris et al have demonstrated that inhibition of GAPDH activity by HNO decreases glycolysis and induces subsequent downregulation of HIF-1a protein expression, thus leading to reduced angiogenesis and tumor growth (107). A recent study has revealed that several genes are uniquely expressed in human breast cancer cells in response to HNO donors, such as miR-21, heat shock protein 70, CSE, and interleukin-24 (25). These findings give new insight into the possible targets by HNO in breast cancer cells.…”

“…HNO is also found to suppress PARP activity (136); this might improve the efficacy of the chemotherapies and radiation therapies. Moreover, in HNOtreated human breast cancer cells, the expression of CSE, TXNIP, and IL-24 was downregulated, while the miR-21 and HSP70 levels were upregulated, all of which may synergistically contribute to its anticancer effects (25). HIF-1a, hypoxia-inducible factor-1a; IL, interleukin; PARP, poly (ADP-ribose) polymerase; VEGF, vascular endothelial growth factor.…”