SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment

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Title
SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment
Author(s)
S W Hong; S H Lee; J H Moon; J J Hwang; D E Kim; E Ko; H S Kim; Ik-Jun Cho; Jong Soon Kang; D J Kim; J E Kim; J S Shin; D J Jung; Y J Jeong; B J Cho; T W Kim; J S Lee; J S Kang; Y I Hwang; D Y Noh; D H Jin; W J Lee
Bibliographic Citation
Oncogene, vol. 32, no. 12, pp. 1508-1517
Publication Year
2013
Abstract
L-ascorbate (L-ascorbic acid, vitamin C) clearly has an inhibitory effect on cancer cells. However, the mechanism underlying differential sensitivity of cancer cells from same tissue to L-ascorbate is yet to be clarified. Here, we demonstrate that L-ascorbate has a selective killing effect, which is influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human breast cancer cells. Treatment of human breast cancer cells with L-ascorbate differentially induced cell death, dependent on the SVCT-2 protein level. Moreover, knockdown of endogenous SVCT-2 via RNA interference in breast cancer cells expressing high levels of the protein induced resistance to L-ascorbate treatment, whereas transfection with SVCT-2 expression plasmids led to enhanced L-ascorbate chemosensitivity. Surprisingly, tumor regression by L-ascorbate administration in mice bearing tumor cell xenograft also corresponded to the SVCT-2 protein level. Interestingly, SVCT-2 expression was absent or weak in normal tissues, but strongly detected in tumor samples obtained from breast cancer patients. In addition, enhanced chemosensitivity to L-ascorbate occurred as a result of caspase-independent autophagy, which was mediated by beclin-1 and LC3 II. In addition, treatment with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, suppressed the induction of beclin-1 and LC3 II, implying that the differential SVCT-2 protein-dependent L-ascorbate uptake was attributable to intracellular ROS induced by L-ascorbate, subsequently leading to autophagy. These results suggest that functional SVCT-2 sensitizes breast cancer cells to autophagic damage by increasing the L-ascorbate concentration and intracellular ROS production and furthermore, SVCT-2 in breast cancer may act as an indicator for commencing L-ascorbate treatment.
Keyword
autophagyBeclin-1L-ascorbateLC3ROSSVCT-2
ISSN
0950-9232
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/onc.2012.176
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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