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.
journal_name
Oncogenejournal_title
Oncogeneauthors
Hong SW,Lee SH,Moon JH,Hwang JJ,Kim DE,Ko E,Kim HS,Cho IJ,Kang JS,Kim DJ,Kim JE,Shin JS,Jung DJ,Jeong YJ,Cho BJ,Kim TW,Lee JS,Kang JS,Hwang YI,Noh DY,Jin DH,Lee WJdoi
10.1038/onc.2012.176subject
Has Abstractpub_date
2013-03-21 00:00:00pages
1508-17issue
12eissn
0950-9232issn
1476-5594pii
onc2012176journal_volume
32pub_type
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