Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells by Upregulating the Expression of RASSF1 and CDKN1A

Abstract

Nitric oxide (NO) is implicated in several biological processes, including cancer progression. At low concentrations, it promotes cell survival and tumor progression, and at high concentrations it causes apoptosis and cell death. Until now, the impact of NO donors has not been investigated on human endometrial tumors. Four cancer cell lines were exposed to different concentrations of DETA/NO for 24 to 120 h. The effects of DETA/NO on cell proliferation and invasion were determined utilizing MTS and Boyden chamber assays, respectively. The DETA/NO induced a dose and time-dependent reduction in cell viability by the activation of caspase-3 and cell cycle arrest at the G0/G1 phase that was associated with the attenuated expression of cyclin-D1 and D3. Furthermore, the reduction in the amount of CD133-expressing cancer stem-like cell subpopulation was observed following DETA/NO treatment of cells, which was associated with a decreased expression of stem cell markers and attenuation of cell invasiveness. To understand the mechanisms by which DETA/NO elicits anti-cancer effects, RNA sequencing (RNA-seq) was used to ascertain alterations in the transcriptomes of human endometrial cancer cells. RNA-seq analysis revealed that 14 of the top 21 differentially expressed genes were upregulated and seven were downregulated in endometrial cancer cells with DETA/NO. The genes that were upregulated in all four cell lines with DETA/NO were the tumor suppressors Ras association domain family 1 isoform A (RASSF1) and Cyclin-dependent kinase inhibitor 1A (CDKN1A). The expression patterns of these genes were confirmed by Western blotting. Taken together, the results provide the first evidence in support of the anti-cancer effects of DETA/NO in endometrial cancer.

Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes

“…These cells in their functional state also produce increased levels of TNFα and iNOS, which contribute to the killing of tumor cells. Nitric oxide production is associated with decreased cancer progression, metastasis and differentiation [ 30 , 31 , 48 ]; however, its role in OVCA chemoresistance is less explored. We demonstrated that M1 macrophage-derived, NO-sensitized, chemoresistant OVCA cell to CDDP-induced death by upregulating ROS production and reducing GSH synthesis.…”

“…These findings are consistent with other reports that have shown iNOS expression in OVCA as a favorable prognostic indicator of disease-related survival [ 30 ]. In other reports, nitric oxide donors have been shown to induce cancer cell death by upregulating the expression of RASSF1 and CDKN1A [ 48 ], activating caspase 8/3 [ 49 ] and regulating anti-apoptotic BCL-2 family members [ 50 ]. Whether NO-induced ROS accumulation results in the activation of other pro-apoptotic genes requires further investigation.…”

Recent Developments in Pharmacological Effect, Mechanism and Application Prospect of Diazeniumdiolates

“…Therefore, b-Gal NONOate is a promising prodrug for targeting intracellular NO, which is expected to become a potential therapeutic drug for cancer ETA/NO dose-and time-dependently induced the cell viability of human endometrial tumors. The mechanism is activating caspase-3 and arresting cell cycle at the G0/G1 phase, associated with attenuating the expression of cyclin-D1 and D3 (Waheed et al, 2019).…”

Progesterone receptor inhibits the proliferation and invasion of endometrial cancer cells by up regulating Krüppel-like factor 9

“…The molecular mechanisms of development of EC are not fully understood. Although many oncogenes and tumor suppressors have been identified as key players underlying tumorigenesis of EC ( 4 - 6 ), however, almost no commonly-accepted biomarkers have been established to facilitate the comprehensive management of EC patients. Therefore, understanding the molecular events underlying endometrial carcinogenesis and identifying new biomarkers and therapeutic targets will be important.…”