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Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells by Upregulating the Expression of RASSF1 and CDKN1A.
Molecules 2019; 24(20)M

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+Show Affiliations

Department of Obstetrics & Gynecology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. waheed1@umbc.edu.Molecular Mechanism Section, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA. robert.cheng2@nih.gov.Department of Obstetrics & Gynecology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. yovanni.casablanca.mil@mail.mil. Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. yovanni.casablanca.mil@mail.mil. John P. Murtha Cancer Center, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. yovanni.casablanca.mil@mail.mil.Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. george.maxwell@inova.org. John P. Murtha Cancer Center, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. george.maxwell@inova.org. Department of Obstetrics & Gynecology, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042, USA. george.maxwell@inova.org.Molecular Mechanism Section, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA. wink@mail.nih.gov.Department of Obstetrics & Gynecology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. viqar.syed@usuhs.edu. John P. Murtha Cancer Center, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA. viqar.syed@usuhs.edu. Department of Molecular and Cell Biology, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. viqar.syed@usuhs.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31623109

Citation

Waheed, Sana, et al. "Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells By Upregulating the Expression of RASSF1 and CDKN1A." Molecules (Basel, Switzerland), vol. 24, no. 20, 2019.
Waheed S, Cheng RY, Casablanca Y, et al. Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells by Upregulating the Expression of RASSF1 and CDKN1A. Molecules. 2019;24(20).
Waheed, S., Cheng, R. Y., Casablanca, Y., Maxwell, G. L., Wink, D. A., & Syed, V. (2019). Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells by Upregulating the Expression of RASSF1 and CDKN1A. Molecules (Basel, Switzerland), 24(20), doi:10.3390/molecules24203722.
Waheed S, et al. Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells By Upregulating the Expression of RASSF1 and CDKN1A. Molecules. 2019 Oct 16;24(20) PubMed PMID: 31623109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nitric Oxide Donor DETA/NO Inhibits the Growth of Endometrial Cancer Cells by Upregulating the Expression of RASSF1 and CDKN1A. AU - Waheed,Sana, AU - Cheng,Robert Ys, AU - Casablanca,Yovanni, AU - Maxwell,G Larry, AU - Wink,David A, AU - Syed,Viqar, Y1 - 2019/10/16/ PY - 2019/08/09/received PY - 2019/10/09/revised PY - 2019/10/12/accepted PY - 2019/10/19/entrez PY - 2019/10/19/pubmed PY - 2019/10/19/medline KW - anticancer KW - cancer stem-like cells KW - invasion KW - nitric oxide KW - tumor growth KW - tumor suppressor JF - Molecules (Basel, Switzerland) JO - Molecules VL - 24 IS - 20 N2 - 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. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/31623109/Nitric_Oxide_Donor_DETA/NO_Inhibits_the_Growth_of_Endometrial_Cancer_Cells_by_Upregulating_the_Expression_of_RASSF1_and_CDKN1A L2 - http://www.mdpi.com/resolver?pii=molecules24203722 DB - PRIME DP - Unbound Medicine ER -