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Clinical and Translational Oncology

, Volume 21, Issue 4, pp 404–411 | Cite as

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

  • H. Guo
  • Z. Xiang
  • Y. Zhang
  • D. SunEmail author
Research Article
  • 143 Downloads

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.

Keywords

6PGD Cervical cancer Physcion AMPK RhoA Rac1 

Notes

Acknowledgement

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

Compliance of ethical standards

Conflicts of interest

All authors declare no conflicts of interests.

Research involving human participants and/or animals

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

Informed consent

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

Supplementary material

12094_2018_1937_MOESM1_ESM.doc (251 kb)
Supplementary material 1 (DOC 251 kb)

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.CrossRefGoogle Scholar
  2. 2.
    Zhu H, Luo H, Zhang W, Shen Z, Hu X, Zhu X. Molecular mechanisms of cisplatin resistance in cervical cancer. Drug Des Devel Ther. 2016;10:1885–95.CrossRefGoogle Scholar
  3. 3.
    Chen J, Xiong J, Liu H, Chernenko G, Tang SC. Distinct BAG-1 isoforms have different anti-apoptotic functions in BAG-1-transfected C33A human cervical carcinoma cell line. Oncogene. 2002;21(46):7050–9.CrossRefGoogle Scholar
  4. 4.
    Chao CC. Enhanced excision repair of DNA damage due to cis-diamminedichloroplatinum(II) in resistant cervix carcinoma HeLa cells. Eur J Pharmacol. 1994;268(3):347–55.CrossRefGoogle Scholar
  5. 5.
    Qureshi R, Arora H, Rizvi MA. EMT in cervical cancer: its role in tumour progression and response to therapy. Cancer Lett. 2015;356(2):321–31.CrossRefGoogle Scholar
  6. 6.
    Chang B, Kim J, Jeong D, Jeong Y, Jeon S, Jung SI, et al. Klotho inhibits the capacity of cell migration and invasion in cervical cancer. Oncol Rep. 2012;28(3):1022–8.CrossRefGoogle Scholar
  7. 7.
    Perez-Plasencia C, Duenas-Gonzalez A, Alatorre-Tavera B. Second hit in cervical carcinogenesis process: involvement of wnt/beta catenin pathway. Int Arch Med. 2008;1(1):10.CrossRefGoogle Scholar
  8. 8.
    Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.CrossRefGoogle Scholar
  9. 9.
    Shan C, Elf S, Ji Q, Kang HB, Zhou L, Hitosugi T, et al. Lysine acetylation activates 6-phosphogluconate dehydrogenase to promote tumor growth. Mol Cell. 2014;55(4):552–65.CrossRefGoogle Scholar
  10. 10.
    Nordenberg J, Aviram R, Beery E, Stenzel KH, Novogrodsky A. Inhibition of 6-phosphogluconate dehydrogenase by glucose 1,6-diphosphate in human normal and malignant colon extracts. Cancer Lett. 1984;23(2):193–9.CrossRefGoogle Scholar
  11. 11.
    Yang X, Peng X, Huang J. Inhibiting 6-phosphogluconate dehydrogenase selectively targets breast cancer through AMPK activation. Clin Transl Oncol. 2018.  https://doi.org/10.1007/s12094-018-1833-4.Google Scholar
  12. 12.
    Giusti L, Iacconi P, Ciregia F, Giannaccini G, Donatini GL, Basolo F, et al. Fine-needle aspiration of thyroid nodules: proteomic analysis to identify cancer biomarkers. J Proteome Res. 2008;7(9):4079–88.CrossRefGoogle Scholar
  13. 13.
    Zheng W, Feng Q, Liu J, Guo Y, Gao L, Li R, et al. Inhibition of 6-phosphogluconate dehydrogenase reverses cisplatin resistance in ovarian and lung cancer. Front Pharmacol. 2017;8:421.CrossRefGoogle Scholar
  14. 14.
    Elf S, Lin R, Xia S, Pan Y, Shan C, Wu S, et al. Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin. Oncogene. 2017;36(2):254–62.CrossRefGoogle Scholar
  15. 15.
    Chan B, VanderLaan PA, Sukhatme VP. 6-Phosphogluconate dehydrogenase regulates tumor cell migration in vitro by regulating receptor tyrosine kinase c-Met. Biochem Biophys Res Commun. 2013;439(2):247–51.CrossRefGoogle Scholar
  16. 16.
    Lin R, Elf S, Shan C, Kang HB, Ji Q, Zhou L, et al. 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat Cell Biol. 2015;17(11):1484–96.CrossRefGoogle Scholar
  17. 17.
    Higareda-Almaraz JC, Enriquez-Gasca Mdel R, Hernandez-Ortiz M, Resendis-Antonio O, Encarnacion-Guevara S. Proteomic patterns of cervical cancer cell lines, a network perspective. BMC Syst Biol. 2011;5:96.CrossRefGoogle Scholar
  18. 18.
    Fogarty S, Hardie DG. Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim Biophys Acta. 2010;1804(3):581–91.CrossRefGoogle Scholar
  19. 19.
    Ridley AJ. Rho GTPase signalling in cell migration. Curr Opin Cell Biol. 2015;36:103–12.CrossRefGoogle Scholar
  20. 20.
    Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, et al. Combination therapy in combating cancer. Oncotarget. 2017;8(23):38022–43.Google Scholar
  21. 21.
    Bonham DG. A new test for the diagnosis of gynaecological cancer, 6-phosphogluconate dehydrogenase activity in vaginal fluid. Triangle Sandoz J Med Sci. 1964;7:157–62.Google Scholar
  22. 22.
    Bell JL, Egerton ME. 6-phosphogluconate dehydrogenase estimation in vaginal fluid in the diagnosis of cervical cancer. J Obstet Gynaecol Br Commonw. 1965;72:603–9.CrossRefGoogle Scholar
  23. 23.
    Hoffman RL, Merritt JW. 6-Phosphogluconate dehydrogenase in uterine cancer detection. Am J Obstet Gynecol. 1965;92:650–7.CrossRefGoogle Scholar
  24. 24.
    Yan Y, Tsukamoto O, Nakano A, Kato H, Kioka H, Ito N, et al. Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5. Nat Commun. 2015;6:6137.CrossRefGoogle Scholar
  25. 25.
    Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13(9):1016–23.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyXiangyang No. 1 People’s Hospital, Hubei University of MedicineXiangyangChina
  2. 2.Department of PathologyXiangyang No. 1 People’s Hospital, Hubei University of MedicineXiangyangChina
  3. 3.Department of PharmacyXiangyang Maternity and Child Health Care HospitalXiangyangChina
  4. 4.Department of Obstetrics and GynecologyHanchuan People’s HospitalHanchuan, XiaoganChina

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