维生素C能杀死乳腺癌细胞

乳腺癌中的SVCT-2作为L -抗坏血酸治疗的指标

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

　

　

癌基因。2013年3月21日;32(12):1508-17。doi:10.1038 / onc.2012.176。2012年6月4日Hong SW1, 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 WJ。作者信息1韩国首尔国立大学医学院解剖与肿瘤免疫医学研究中心。

摘要l -抗坏血酸(L -抗坏血酸，维生素C)显然对癌细胞有抑制作用。然而，癌细胞对L -抗坏血酸的敏感性差异的机制尚不清楚。

在此，我们证明了L -抗坏血酸具有选择性杀伤作用，这是受钠依赖性维生素C转运蛋白2 (SVCT-2)在人类乳腺癌细胞中的影响。L -抗坏血酸诱导人乳腺癌细胞死亡的治疗依赖于SVCT-2蛋白水平。此外，通过RNA干扰抑制内源性SVCT-2在表达高水平的蛋白的乳腺癌细胞诱导对L -抗坏血酸治疗的耐药性，而转染SVCT-2表达质粒导致L-抗坏血酸化疗敏感性增强。令人惊讶的是，L -抗坏血酸治疗异种移植瘤小鼠的肿瘤消退也与SVCT-2蛋白水平一致。有趣的是，正常组织中SVCT-2表达缺失或表达不足，但在乳腺癌患者的肿瘤样本中检测到较强的表达。

此外，与caspase无关的自噬是由beclin-1和LC3介导的，因此对L -抗坏血酸的化学敏感性增强。此外，活性氧清除剂N-乙酰- L-半胱氨酸(N-acetyl-L-cysteine, ROS)处理抑制beclin-1和LC3的诱导，提示差异SVCT-2蛋白依赖性的L-抗坏血酸摄取可归因于L-抗坏血酸诱导的细胞内ROS，进而导致自噬。这些结果表明，功能性SVCT-2通过增加L -抗坏血酸浓度和细胞内ROS的生成，使乳腺癌细胞对自噬损伤敏感，而且，乳腺癌中的SVCT-2可能作为开始L-抗坏血酸治疗的指标。

　

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Oncogene. 2013 Mar 21;32(12):1508-17. doi: 10.1038/onc.2012.176. Epub 2012 Jun 4.
SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment.
Hong SW1, 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 WJ.
Author information

1
Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
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.
PMID: 22665050 DOI: 10.1038/onc.2012.176
https://www.ncbi.nlm.nih.gov/pubmed/22665050