Abstract
Genomic loss of 5-hydroxymethylcytosine (5hmC) accompanies malignant cellular transformation in breast cancer. Vitamin C serves as a cofactor for TET methylcytosine dioxygenases to increase 5hmC generation. Here we show that the transcription of SVCT2, a major vitamin C transporter, was decreased in human breast cancers (113 cases) compared to normal breast tissues from the same patients. A decreased SVCT2 expression was also observed in breast cancer cell lines. Treatment with vitamin C (100 μM) increased the 5hmC content in MDA-MB-231 breast cancer cells and markedly altered the transcriptome. The vitamin C treatment induced apoptosis in MDA-MB-231 cells, which was verified in two additional breast cancer cell lines. This pro-apoptotic effect of vitamin C appeared to be mediated by TRAIL, a known apoptosis inducer. Vitamin C upregulated TRAIL transcripts (2.3-fold increase) and increased TRAIL protein levels. The upregulation of TRAIL by vitamin C was largely abolished by siRNAs targeting TETs and anti-TRAIL antibody abrogated the induction of apoptosis. Furthermore, the apoptosis promoted by vitamin C was associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, these results suggest a potential role of physiological doses of vitamin C in breast cancer prevention and treatment.
| Original language | English (US) |
|---|---|
| Article number | 5306 |
| Journal | Scientific Reports |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
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Vitamin C promotes apoptosis in breast cancer cells by increasing TRAIL expression. / Sant, David W.; Mustafi, Sushmita; Gustafson, Christopher B.; Chen, Joshua; Slingerland, Joyce M; Wang, Gaofeng.
In: Scientific Reports, Vol. 8, No. 1, 5306, 01.12.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Vitamin C promotes apoptosis in breast cancer cells by increasing TRAIL expression
AU - Sant, David W.
AU - Mustafi, Sushmita
AU - Gustafson, Christopher B.
AU - Chen, Joshua
AU - Slingerland, Joyce M
AU - Wang, Gaofeng
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Genomic loss of 5-hydroxymethylcytosine (5hmC) accompanies malignant cellular transformation in breast cancer. Vitamin C serves as a cofactor for TET methylcytosine dioxygenases to increase 5hmC generation. Here we show that the transcription of SVCT2, a major vitamin C transporter, was decreased in human breast cancers (113 cases) compared to normal breast tissues from the same patients. A decreased SVCT2 expression was also observed in breast cancer cell lines. Treatment with vitamin C (100 μM) increased the 5hmC content in MDA-MB-231 breast cancer cells and markedly altered the transcriptome. The vitamin C treatment induced apoptosis in MDA-MB-231 cells, which was verified in two additional breast cancer cell lines. This pro-apoptotic effect of vitamin C appeared to be mediated by TRAIL, a known apoptosis inducer. Vitamin C upregulated TRAIL transcripts (2.3-fold increase) and increased TRAIL protein levels. The upregulation of TRAIL by vitamin C was largely abolished by siRNAs targeting TETs and anti-TRAIL antibody abrogated the induction of apoptosis. Furthermore, the apoptosis promoted by vitamin C was associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, these results suggest a potential role of physiological doses of vitamin C in breast cancer prevention and treatment.
AB - Genomic loss of 5-hydroxymethylcytosine (5hmC) accompanies malignant cellular transformation in breast cancer. Vitamin C serves as a cofactor for TET methylcytosine dioxygenases to increase 5hmC generation. Here we show that the transcription of SVCT2, a major vitamin C transporter, was decreased in human breast cancers (113 cases) compared to normal breast tissues from the same patients. A decreased SVCT2 expression was also observed in breast cancer cell lines. Treatment with vitamin C (100 μM) increased the 5hmC content in MDA-MB-231 breast cancer cells and markedly altered the transcriptome. The vitamin C treatment induced apoptosis in MDA-MB-231 cells, which was verified in two additional breast cancer cell lines. This pro-apoptotic effect of vitamin C appeared to be mediated by TRAIL, a known apoptosis inducer. Vitamin C upregulated TRAIL transcripts (2.3-fold increase) and increased TRAIL protein levels. The upregulation of TRAIL by vitamin C was largely abolished by siRNAs targeting TETs and anti-TRAIL antibody abrogated the induction of apoptosis. Furthermore, the apoptosis promoted by vitamin C was associated with Bax and caspases activation, Bcl-xL sequestration, and cytochrome c release. Taken together, these results suggest a potential role of physiological doses of vitamin C in breast cancer prevention and treatment.
UR - http://www.scopus.com/inward/record.url?scp=85044609635&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044609635&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-23714-7
DO - 10.1038/s41598-018-23714-7
M3 - Article
C2 - 29593282
AN - SCOPUS:85044609635
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 5306
ER -