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Expression of PDK1 in malignant pheochromocytoma as a new promising potential therapeutic target

  • X. Zhang
  • Z. YuEmail author
Research Article

Abstract

Purpose

Phosphoinositide-dependent kinase 1 (PDK1) is highly expressed in many solid tumors. And several studies have demonstrated that PDK1 has been an emerging and promising target for anti-cancer therapies. However, the role of PDK1 has not been studied so far in malignant pheochromocytoma (PCC).

Methods

In this study, immunohistochemical staining was performed to investigate the protein level of PDK1 in 63 PCC tissue samples, of which 49 were benign and 14 were malignant. In addition, we evaluated the effect of inhibition of PDK1 with siRNA on cell growth, apoptosis and invasive capacity in PC12 cells and identified the underlying mechanisms.

Results

We found that PDK1 was overexpressed in malignant PCC tissues, and knockdown of PDK1 with siRNA significantly inhibited cell proliferation, increased apoptosis induction, and attenuated cell migration and invasive capacity in PC12 cells. We also showed that knockdown of PDK1 significantly reduced the phosphorylation of Akt at threonine 308 (p-Akt T308) but did not alter the serine phosphorylation of Akt on the S473 site (p-Akt S473). Furthermore, we found that the p-Akt expression was noticeably decreased after knockdown of PDK1, but the t-Akt expression did not show a significant decrease.

Conclusion

We have demonstrated for the first time that PDK1 is overexpressed in human malignant PCC and plays an important role in the malignant biological behaviors of PC12 cell. Specifically, we have revealed that knockdown of PDK1 could attenuate activation of the Akt signaling. These data suggest that PDK1 could be a new promising potential therapeutic target in human cancer treatment for malignant PCC.

Keywords

Phosphoinositide-dependent kinase 1 PDK1 Adrenal gland Malignant pheochromocytoma Target 

Notes

Acknowledgements

This work was supported by Huashan Hospital Affiliated to Fudan University.

Authors’ contributions

ZY conceived and designed the experiments. XZ performed the experiments. ZY coordinated the research and analyzed the data. XZ wrote the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81502315).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

This study was in accordance with the ethical standards and was approved by The First Affiliated Hospital of Wenzhou Medical University.

Ethical statement

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Availability of data and materials

The datasets generated and/or analysed during this study are available from the first author and corresponding author on reasonable request.

Consent for publication

Not applicable.

References

  1. 1.
    Eisenhofer G, Lenders JW, Siegert G, Bornstein SR, Friberg P, Milosevic D, et al. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer. 2012;48(11):1739–49.CrossRefGoogle Scholar
  2. 2.
    Lenders JWM, Eisenhofer G. Update on modern management of pheochromocytoma and paraganglioma. Endocrinol Metab (Seoul). 2017;32(2):152–61.CrossRefGoogle Scholar
  3. 3.
    Druce MR, Kaltsas GA, Fraenkel M, Gross DJ, Grossman AB. Novel and evolving therapies in the treatment of malignant phaeochromocytoma: experience with the mTOR inhibitor everolimus (RAD001). Horm Metab Res. 2009;41(9):697–702.CrossRefGoogle Scholar
  4. 4.
    Jimenez C, Rohren E, Habra MA, Rich T, Jimenez P, Ayala-Ramirez M, et al. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep. 2013;15(4):356–71.CrossRefGoogle Scholar
  5. 5.
    Parenti G, Zampetti B, Rapizzi E, Ercolino T, Giachè V, Mannelli M. Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma. J Oncol. 2012;2012:872713.CrossRefGoogle Scholar
  6. 6.
    Gagliardi PA, Puliafito A, Primo L. PDK1: at the crossroad of cancer signaling pathways. Semin Cancer Biol. 2018;48:27–35.CrossRefGoogle Scholar
  7. 7.
    Emmanouilidi A, Falasca M. Targeting PDK1 for chemosensitization of cancer cells. Cancers (Basel). 2017;9(10):E140.CrossRefGoogle Scholar
  8. 8.
    Wang Y, Fu L, Cui M, Wang Y, Xu Y, Li M, et al. Amino acid transporter SLC38A3 promotes metastasis of non-small cell lung cancer cells by activating PDK1. Cancer Lett. 2017;1(393):8–15.CrossRefGoogle Scholar
  9. 9.
    Lohneis P, Darb-Esfahani S, Dietel M, Braicu I, Sehouli J, Arsenic R. PDK1 is expressed in ovarian serous carcinoma and correlates with improved survival in high-grade tumors. Anticancer Res. 2015;35(11):6329–34.Google Scholar
  10. 10.
    Zabkiewicz J, Pearn L, Hills RK, Morgan RG, Tonks A, Burnett AK, et al. The PDK1 master kinase is over-expressed in acute myeloid leukemia and promotes PKC-mediated survival of leukemic blasts. Haematologica. 2014;99(5):858–64.CrossRefGoogle Scholar
  11. 11.
    Du J, Yang M, Chen S, Li D, Chang Z, Dong Z. PDK1 promotes tumor growth and metastasis in a spontaneous breast cancer model. Oncogene. 2016;35(25):3314–23.CrossRefGoogle Scholar
  12. 12.
    Zhang X, Wang X, Xu T, Zhong S, Shen Z. Targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant pheochromocytoma. Tumour Biol. 2015;36(7):5273–81.CrossRefGoogle Scholar
  13. 13.
    Zhang JY, Tao LY, Liang YJ, Chen LM, Mi YJ, Zheng LS, et al. Anthracenedione derivatives as anticancer agents isolated from secondary metabolites of the mangrove endophytic fungi. Mar Drugs. 2010;8:1469–81.CrossRefGoogle Scholar
  14. 14.
    Suber TL, Nikolli I, O’Brien ME, Londino J, Zhao J, Chen K, et al. FBXO17 promotes cell proliferation through activation of Akt in lung adenocarcinoma cells. Respir Res. 2018;19(1):206.CrossRefGoogle Scholar
  15. 15.
    Jouali F, Marchoudi N, Talbi S, Bilal B, El Khasmi M, Rhaissi H, et al. Detection of PIK3/AKT pathway in Moroccan population with triple negative breast cancer. BMC Cancer. 2018;18(1):900.CrossRefGoogle Scholar
  16. 16.
    Hisamatsu Y, Oki E, Otsu H, Ando K, Saeki H, Tokunaga E, et al. Effect of EGFR and p-AKT overexpression on chromosomal instability in gastric cancer. Ann Surg Oncol. 2016;23(6):1986–92.CrossRefGoogle Scholar
  17. 17.
    Coant N, García-Barros M, Zhang Q, Obeid LM, Hannun YA. AKT as a key target for growth promoting functions of neutral ceramidase in colon cancer cells. Oncogene. 2018;37(28):3852–63.CrossRefGoogle Scholar
  18. 18.
    Brasseur K, Gévry N, Asselin E. Chemoresistance and targeted therapies in ovarian and endometrial cancers. Oncotarget. 2017;8(3):4008–42.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2019

Authors and Affiliations

  1. 1.Department of UrologyHuashan Hospital Affiliated to Fudan UniversityShanghaiChina
  2. 2.Department of UrologyThe First Affiliated Hospital of Wenzhou Medical UniversityWenzhouChina

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