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

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.

• Authors: S-W Hong, S-H Lee, J-H Moon, J J Hwang, D E Kim, E Ko, H-S Kim, I J Cho, J S 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
• Journal: Oncogene (Oncogene) Vol. 32 Issue 12 Pg. 1508-17 (Mar 21 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 22665050 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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