Elevation of soluble guanylate cyclase suppresses proliferation and survival of human breast cancer cells

Hui Chin Wen, Chih Pin Chuu, Chen Yu Chen, Shine Gwo Shiah, Hsing Jien Kung, Kuang Liang King, Liang Chen Su, Shi Chuan Chang, Chung Ho Chang

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Nitric oxide (NO) is an essential signaling molecule in biological systems. Soluble guanylate cyclase (sGC), composing of α1 and β1 subunit, is the receptor for NO. Using radioimmunoassay, we discovered that activation of sGC by treatment with bradykinin or sodium nitroprusside (SNP) is impaired in MCF-7 and MDA-MB-231 breast cancer cells as compared to normal breast epithelial 184A1 cells. The 184A1 cells expressed both sGC α1 and sGCβ1 mRNAs. However, levels of sGCβ1 mRNAs were relatively lower in MCF-7 cells while both mRNA of sGC subunits were absent in MDA-MB-231 cells. Treatment with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) increased mRNA levels of both sGCα1 and sGCβ1 in MDA-MB-231 cells but only sGCβ1 mRNAs in MCF-7 cells. The 5-aza-dC treatment increased the SNP-induced cGMP production in MCF-7 and MDA-MB-231, but not in 184A1 cells. Bisulfite sequencing revealed that the promoter of sGCα1 in MDA-MB-231 cells and promoter of sGCβ1 in MCF-7 cells were methylated. Promoter hypermethylation of sGCα1 and sGCβ1 was found in 1 out of 10 breast cancer patients. Over-expression of both sGC subunits in MDA-MB-231 cells induced apoptosis and growth inhibition in vitro as well as reduced tumor incidence and tumor growth rate of MDA-MB-231 xenografts in nude mice. Elevation of sGC reduced protein abundance of Bcl-2, Bcl-xL, Cdc2, Cdc25A, Cyclin B1, Cyclin D1, Cdk6, c-Myc, and Skp2 while increased protein expression of p53. Our study demonstrated that down-regulation of sGC, partially due to promoter methylation, provides growth and survival advantage in human breast cancer cells.

Original languageEnglish
Article numbere0125518
JournalPLoS One
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 1 2015
Externally publishedYes

Fingerprint

guanylate cyclase
Guanylate Cyclase
breast neoplasms
decitabine
Cells
Breast Neoplasms
Messenger RNA
Survival
Nitroprusside
MCF-7 Cells
cells
Tumors
Nitric Oxide
promoter regions
Cyclin B1
cyclins
Methylation
Cyclin D1
Methyltransferases
Bradykinin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Elevation of soluble guanylate cyclase suppresses proliferation and survival of human breast cancer cells. / Wen, Hui Chin; Chuu, Chih Pin; Chen, Chen Yu; Shiah, Shine Gwo; Kung, Hsing Jien; King, Kuang Liang; Su, Liang Chen; Chang, Shi Chuan; Chang, Chung Ho.

In: PLoS One, Vol. 10, No. 4, e0125518, 01.04.2015.

Research output: Contribution to journalArticle

Wen, HC, Chuu, CP, Chen, CY, Shiah, SG, Kung, HJ, King, KL, Su, LC, Chang, SC & Chang, CH 2015, 'Elevation of soluble guanylate cyclase suppresses proliferation and survival of human breast cancer cells', PLoS One, vol. 10, no. 4, e0125518. https://doi.org/10.1371/journal.pone.0125518
Wen, Hui Chin ; Chuu, Chih Pin ; Chen, Chen Yu ; Shiah, Shine Gwo ; Kung, Hsing Jien ; King, Kuang Liang ; Su, Liang Chen ; Chang, Shi Chuan ; Chang, Chung Ho. / Elevation of soluble guanylate cyclase suppresses proliferation and survival of human breast cancer cells. In: PLoS One. 2015 ; Vol. 10, No. 4.
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