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    題名: Elevation of soluble guanylate cyclase suppresses proliferation and survival of human breast cancer cells
    作者: Wen, HC;Chuu, CP;Chen, CY;Shiah, SG;Kung, HJ;King, KL;Su, LC;Chang, SC;Chang, CH
    貢獻者: Institute of Cellular and Systems Medicine;National Institute of Cancer Research;Institute of Molecular and Genomic Medicine
    摘要: Nitric oxide (NO) is an essential signaling molecule in biological systems. Soluble guanylate cyclase (sGC), composing of alpha1 and beta1 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 alpha1 and sGCbeta1 mRNAs. However, levels of sGCbeta1 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 sGCalpha1 and sGCbeta1 in MDA-MB-231 cells but only sGCbeta1 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 sGCalpha1 in MDA-MB-231 cells and promoter of sGCbeta1 in MCF-7 cells were methylated. Promoter hypermethylation of sGCalpha1 and sGCbeta1 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.
    日期: 2015-04-30
    關聯: PLoS ONE. 2015 Apr 30;10(4):Article number e0125518.
    Link to: http://dx.doi.org/10.1371/journal.pone.0125518
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1932-6203&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000353713100096
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84949528212
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