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Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation

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Abstract

Purpose

6-phosphogluconate dehydrogenase (6PGD), a key enzyme of the oxidative pentose phosphate pathway, is involved in tumor growth and metabolism. Although high 6PGD activity has been shown to be associated with poor prognosis, its role and therapeutic value in breast cancer remain unknown.

Methods

The levels and roles of 6PGD were analyzed in breast cancer cells and their normal counterparts. The underlying mechanisms of 6PGD’s roles are also analyzed.

Results

We found that 6PGD is aberrantly activated in breast cancer as shown by its increased transcriptional and translational levels as well as enzyme activity in breast cancer tissues and cell lines compared to normal counterparts. Although similar degree of enzyme activity inhibition was achieved in both breast cancer and normal breast cells, 6PGD inhibition by siRNA-mediated knockdown or pharmacological inhibitor physcion is more effective in inhibiting growth and survival in breast cancer than normal breast cells. Moreover, inhibiting 6PGD significantly sensitizes breast cancer response to chemotherapeutic agents in in vitro cell culture system and in vivo xenograft breast cancer model. We further show that 6PGD inhibition activates AMPK and its downstream substrate ACC1, leading to reduction of ACC1 activity and lipid biosynthesis. AMPK depletion significantly reverses the inhibitory effects of physcion in breast cancer cells, confirming that 6PGD inhibition targets breast cancer cell via AMPK activation.

Conclusions

Our work provides experimental evidence on the association of 6PGD with poor prognosis in breast cancer and suggests that 6PGD inhibition may represent a potential therapeutic strategy to augment chemotherapy efficacy in breast cancer.

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Acknowledgements

This work was supported by a research grant provided by Hubei Provincial Health and Family Planning Commission (Grant No. 2016-2017 15).

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Authors and Affiliations

  1. Department of Oncology, Xiangyang No.1 People’s Hospital, Xiangyang, Hubei, China

    Xiaoyu Yang

  2. Department of Pathophysiology, Medical School of Yangtze University, Jingzhou, Hubei, China

    Xiaochun Peng

  3. Department of Integrative Medicine, Medical School of Yangtze University, Jianghan Rd 55, Shashi, Jingzhou, 434000, Hubei, China

    Jiangrong Huang

Authors
  1. Xiaoyu Yang
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  2. Xiaochun Peng
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  3. Jiangrong Huang
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Contributions

XYY and JRH designed the experiments, interpreted the data and wrote the manuscript. XYY, XCP and JRH performed the experiments. All authors approved the final manuscripts.

Corresponding author

Correspondence to Jiangrong Huang.

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Conflict of interest

All authors declare that they have no conflicts of interests.

Informed consent

Breast cancer samples were obtained from patients seen at the Xiangyang No.1 People’s Hospital. Written informed consent was obtained from all patients under institutional review board-approved protocols.

Research involving human participants and/or animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Yang, X., Peng, X. & Huang, J. Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation. Clin Transl Oncol 20, 1145–1152 (2018). https://doi.org/10.1007/s12094-018-1833-4

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  • DOI: https://doi.org/10.1007/s12094-018-1833-4

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