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

Oncogene volume 32, pages 1508–1517 (2013)Cite this article

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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.

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Acknowledgements

This work was supported by Korean Science and Engineering Foundation (KOSEF) through the Tumor Immunity Medical Research Center at Seoul National University College of Medicine (R13-2002-025-02001-0) and by grants from the Korea Health 21 R&D Project, Ministry of Health and Welfare and Family Affairs, Republic of Korea (A062254). We would like to thank Dr Norio Itoh, Osaka University, for providing SVCT-2 antibody; and Dr Tobias P Dick, German Cancer Research Center, for providing redox-probe cDNAs.

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  1. S-W Hong and S-H Lee: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea

    S-W Hong, S-H Lee, J-E Kim, J-S Shin, D-J Jung, Y-J Jeong, J-S Kang, Y-I Hwang, D-H Jin & W J Lee

  2. Institute for Innovate Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    S-W Hong, J-H Moon, J J Hwang, D E Kim, J-S Shin, T-W Kim, J S Lee & D-H Jin

  3. Department of Plastic and Reconstructive Surgery, Paik-Hospital, Inje University, Gyeonggi-do, Republic of Korea

    S-H Lee

  4. Department of Surgery and Cancer Research Institute, Seoul National University, College of Medicine, Seoul, Republic of Korea

    E Ko, H-S Kim & D-Y Noh

  5. Bioevaluation Center, Korea Research Insitute of Bioscience and Biotechnology, Chungbuk, Republic of Korea

    I J Cho & J S Kang

  6. Department of Anatomy, Chung-Ang University, College of Medicine, Seoul, Republic of Korea

    D J Kim & J-E Kim

  7. Department of Ophthalmology, Konkuk University, School of Medicine, Konkuk University Hospital, Seoul, Republic of Korea

    B-J Cho

  8. Department of Oncology, Asan Medical Center, Seoul, Republic of Korea

    T-W Kim & J S Lee

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  1. S-W Hong
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Correspondence to D-H Jin or W J Lee.

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Hong, SW., Lee, SH., Moon, JH. et al. SVCT-2 in breast cancer acts as an indicator for L-ascorbate treatment. Oncogene 32, 1508–1517 (2013). https://doi.org/10.1038/onc.2012.176

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