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

Oncogene. 2013 Mar 21;32(12):1508-17. doi: 10.1038/onc.2012.176. Epub 2012 Jun 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Ascorbic Acid / pharmacokinetics
  • Ascorbic Acid / therapeutic use*
  • Autophagy / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Reactive Oxygen Species / metabolism
  • Sodium-Coupled Vitamin C Transporters / analysis
  • Sodium-Coupled Vitamin C Transporters / physiology*


  • Reactive Oxygen Species
  • SLC23A2 protein, human
  • Sodium-Coupled Vitamin C Transporters
  • Ascorbic Acid
  • Acetylcysteine