SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment.
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.
Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
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D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001205:Ascorbic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000378:metabolism; D060347:Sodium-Coupled Vitamin C Transporters / Q000032:analysis / Q000502:physiology*
D017382:Reactive Oxygen Species; C555163:SLC23A2 protein, human; D060347:Sodium-Coupled Vitamin C Transporters; D001205:Ascorbic Acid; D000111:Acetylcysteine