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.

• Authors: Sana Waheed, Robert Ys Cheng, Yovanni Casablanca, G Larry Maxwell, David A Wink, Viqar Syed
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 24 Issue 20 (Oct 16 2019) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 31623109 (Publication Type: Journal Article)

Chemical References

• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Nitric Oxide Donors
• RASSF1 protein, human
• Tumor Suppressor Proteins
• Nitric Oxide
• Caspases

Topics

• Apoptosis (drug effects)
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Endometrial Neoplasms (genetics)
• Female
• Gene Expression Regulation (drug effects)
• Gene Knockdown Techniques
• Humans
• Nitric Oxide (metabolism)
• Nitric Oxide Donors (pharmacology)
• Stem Cells (drug effects, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)