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Inhibiting 6-phosphogluconate dehydrogenase enhances chemotherapy efficacy in cervical cancer via AMPK-independent inhibition of RhoA and Rac1

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Abstract

Background

The oxidative pentose phosphate pathway (PPP) is essential for cancer metabolism and growth. However, the contribution of 6-phosphogluconate dehydrogenase (6PGD), a key enzyme of PPP, to cervical cancer development remains largely unknown.

Methods

mRNA and protein levels of 6PGD were analyzed in cervical cancer cells and tissues derived from patients and compared to normal counterparts. Using cell culture system and xenograft mouse model, the functions of 6PGD in cervical cancer are determined and its molecular mechanism is analyzed. 6PGD inhibitor physcion and siRNA knockdown were used.

Results

In this work, we demonstrate that 6PGD is aberrantly upregulated and activated in cervical cancer cells and patient tissues compared to normal counterparts. Using different approaches and preclinical models, we show that 6PGD inhibition decreases growth and migration, and enhances chemosensitivity in cervical cancer. Mechanistically, inhibition of 6PGD activates AMP-activated protein kinase (AMPK) and decreases RhoA and Rac1 activities. AMPK depletion significantly reduces the effects of 6PGD inhibition in decreasing RhoA and Rac1 activities, growth and migration in cervical cancer cells.

Conclusions

Our work is the first to demonstrate the aberrant expression of 6PGD and its predominant roles in cervical cancer cell growth and migration, via a AMPK-dependent activation. Our findings suggest 6PGD as a potential therapeutic target to enhance chemosensitivity in cervical cancer.

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Acknowledgement

This work was supported by a research grant provided by Hubei Provincial Science and Technology Commission (Grant no. EK100826).

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Author notes

  1. H. Guo, Z. Xiang and Y. Zhang contributed to this work equally and are co-first authors.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Xiangyang No. 1 People’s Hospital, Hubei University of Medicine, Xiangyang, Hubei, China

    H. Guo

  2. Department of Pathology, Xiangyang No. 1 People’s Hospital, Hubei University of Medicine, Xiangyang, Hubei, China

    Z. Xiang

  3. Department of Pharmacy, Xiangyang Maternity and Child Health Care Hospital, Xiangyang, Hubei, China

    Y. Zhang

  4. Department of Obstetrics and Gynecology, Hanchuan People’s Hospital, Hanchuan, Xiaogan, Hubei, 431600, China

    D. Sun

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  1. H. Guo
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  4. D. Sun
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Correspondence to D. Sun.

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

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Informed consent was obtained from all individual participants included in the study.

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Guo, H., Xiang, Z., Zhang, Y. et al. Inhibiting 6-phosphogluconate dehydrogenase enhances chemotherapy efficacy in cervical cancer via AMPK-independent inhibition of RhoA and Rac1. Clin Transl Oncol 21, 404–411 (2019). https://doi.org/10.1007/s12094-018-1937-x

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  • DOI: https://doi.org/10.1007/s12094-018-1937-x

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