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Increased ceramide production sensitizes breast cancer cell response to chemotherapy

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Background

Advanced breast cancer remains clinically challenging due to its resistance to chemotherapy. To understand the underlying mechanisms of resistance and identify drugable target, the involvement of ceramide metabolism is investigated.

Methods

Ceramide levels in breast cancer tissues derived from 30 patients with stage IV breast cancer before and after chemotherapy were analyzed using liquid chromatography mass spectrometry. mRNA and protein levels of ceramide enzymes were examined using western blot and QRT-PCR. The effects of ceramide analog were investigated using cellular assays and xenograft tumor model.

Results

The results demonstrated that pro-apoptotic ceramide was significantly lower in all patients after chemotherapy, suggesting that downregulation of ceramide is a common feature of breast cancer patients in response to chemotherapy. Molecular characteristics analysis of ceramide indicated C16:0 as the predominant sphingolipid regulated by chemotherapy in breast cancer patients. Mechanistically, ceramide levels were suppressed by chemotherapy via increasing mRNA and protein levels of UDP-glucose ceramide glucosyltransferase (UGCG). Importantly, inhibition of UGCG using siRNA or upregulation of cellular ceramide levels using C2 ceramide alone inhibited proliferation and induced apoptosis of breast cancer cells, and enhanced the inhibitory effects of chemotherapeutic drugs in vitro and in vivo.

Conclusions

This study clearly demonstrated that the decreased ceramide production via up-regulating UGCG was involved in the resistance of breast cancer cells to chemotherapy. Stimulating ceramide or decreasing UGCG can potentially be useful for breast cancer treatment.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81202095) and the Research Fund for the Doctoral Program of Higher Education of China (20120142120053).

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Authors and Affiliations

  1. Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jie Fang Avenue, Wuhan, 430030, China

    Jing Che, Yu Huang & Peng Zhang

  2. College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Jing Che

  3. School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Chuanrui Xu

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  1. Jing Che
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  2. Yu Huang
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Correspondence to Peng Zhang.

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All authors declare no conflicts of interests.

Research involving human participants and/or animals

All procedures involving human participants were performed in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All procedures involving animals were conducted according to the guidelines approved by the Institutional Animal Care and Use Committee of Tongji University.

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Written informed consent was obtained from all individual participants included in the study under institutional review board approved protocols.

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Che, J., Huang, Y., Xu, C. et al. Increased ceramide production sensitizes breast cancer cell response to chemotherapy. Cancer Chemother Pharmacol 79, 933–941 (2017). https://doi.org/10.1007/s00280-017-3292-y

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  • DOI: https://doi.org/10.1007/s00280-017-3292-y

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