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.
Similar content being viewed by others
References
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.
Lenders JWM, Eisenhofer G. Update on modern management of pheochromocytoma and paraganglioma. Endocrinol Metab (Seoul). 2017;32(2):152–61.
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.
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.
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.
Gagliardi PA, Puliafito A, Primo L. PDK1: at the crossroad of cancer signaling pathways. Semin Cancer Biol. 2018;48:27–35.
Emmanouilidi A, Falasca M. Targeting PDK1 for chemosensitization of cancer cells. Cancers (Basel). 2017;9(10):E140.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Brasseur K, Gévry N, Asselin E. Chemoresistance and targeted therapies in ovarian and endometrial cancers. Oncotarget. 2017;8(3):4008–42.
Acknowledgements
This work was supported by Huashan Hospital Affiliated to Fudan University.
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 81502315).
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
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.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhang, X., Yu, Z. Expression of PDK1 in malignant pheochromocytoma as a new promising potential therapeutic target. Clin Transl Oncol 21, 1312–1318 (2019). https://doi.org/10.1007/s12094-019-02055-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-019-02055-5