Skip to main content

Advertisement

SpringerLink
Log in

PDK4 promotes tumorigenesis and cisplatin resistance in lung adenocarcinoma via transcriptional regulation of EPAS1

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

A Correction to this article was published on 15 April 2021

This article has been updated

Abstract

The use of cisplatin for the treatment of non-small cell lung cancer has long been constrained by the rapid acquisition of tumor cell chemoresistance. In the present study, we sought to better elucidate the molecular mechanisms underlying this resistance phenotype. To that end, we assessed gene expression patterns in cisplatin-resistant lung adenocarcinoma cells, revealing pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4) to be the most up-regulated kinase in resistant cells. We further found PDK4 upregulation to be directly linked with the acquisition of chemoresistance, driving enhanced tumor cell growth in vitro and in vivo. In clinical samples, we also found that PDK4 upregulation was detectable in patients with lung adenocarcinoma and that it was correlated with a poorer prognosis for these patients. From a mechanistic perspective, we further determined that PDK4 was able to promote lung adenocarcinoma cell growth and cisplatin resistance at least in part via regulating endothelial PAS domain-containing protein 1 (EPAS1) expression, thus highlighting PDK4 as a potentially viable therapeutic target in efforts to treat lung adenocarcinoma patients that have become resistant to cisplatin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Change history

References

  1. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30. https://doi.org/10.3322/caac.21332

    Article  PubMed  Google Scholar 

  2. Miller KD et al (2016) Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66:271–289. https://doi.org/10.3322/caac.21349

    Article  Google Scholar 

  3. Zappa C, Mousa SA (2016) Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res 5:288–300. https://doi.org/10.21037/tlcr.2016.06.07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fennell DA et al (2016) Cisplatin in the modern era: the backbone of first-line chemotherapy for non-small cell lung cancer. Cancer Treat Rev 44:42–50. https://doi.org/10.1016/j.ctrv.2016.01.003

    Article  CAS  PubMed  Google Scholar 

  5. Gerber DE et al (2017) Treatment design and rationale for a randomized trial of cisplatin and etoposide plus thoracic radiotherapy followed by nivolumab or placebo for locally advanced non-small-cell lung cancer (RTOG 3505). Clin Lung Cancer 18:333–339. https://doi.org/10.1016/j.cllc.2016.10.009

    Article  CAS  PubMed  Google Scholar 

  6. Drayton RM, Catto JW (2012) Molecular mechanisms of cisplatin resistance in bladder cancer. Expert Rev Anticancer Ther 12:271–281. https://doi.org/10.1586/era.11.201

    Article  CAS  PubMed  Google Scholar 

  7. Isozaki H et al (2016) Non-small cell lung cancer cells acquire resistance to the ALK inhibitor alectinib by activating alternative receptor tyrosine kinases. Can Res 76:1506–1516. https://doi.org/10.1158/0008-5472.CAN-15-1010

    Article  CAS  Google Scholar 

  8. Kurokawa H, Arteaga CL (2001) Inhibition of erbB receptor (HER) tyrosine kinases as a strategy to abrogate antiestrogen resistance in human breast cancer. Clin Cancer Res 7:4436s–4442s (discussion 4411s–4412s)

    CAS  PubMed  Google Scholar 

  9. Liu S et al (2014a) Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer. Oncotarget 5:9049–9064. https://doi.org/10.18632/oncotarget.2022

    Article  PubMed  PubMed Central  Google Scholar 

  10. Xing H et al (2005) Effect of the cyclin-dependent kinases inhibitor p27 on resistance of ovarian cancer multicellular spheroids to anticancer chemotherapy. J Cancer Res Clin Oncol 131:511–519. https://doi.org/10.1007/s00432-005-0677-9

    Article  CAS  PubMed  Google Scholar 

  11. Wang J et al (2016) Cyclin-dependent kinase 2 promotes tumor proliferation and induces radio resistance in glioblastoma. Transl Oncol 9:548–556. https://doi.org/10.1016/j.tranon.2016.08.007

    Article  PubMed  PubMed Central  Google Scholar 

  12. Holness MJ, Sugden MC (2003) Regulation of pyruvate dehydrogenase complex activity by reversible phosphorylation. Biochem Soc Trans 31:1143–1151. https://doi.org/10.1042/bst0311143

    Article  CAS  Google Scholar 

  13. Leclerc D et al (2017) Oncogenic role of PDK4 in human colon cancer cells. Br J Cancer 116:930–936. https://doi.org/10.1038/bjc.2017.38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Walter W et al (2015) Altered regulation of PDK4 expression promotes antiestrogen resistance in human breast cancer cells. SpringerPlus 4:689. https://doi.org/10.1186/s40064-015-1444-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dixit D, Ahmad F, Ghildiyal R, Joshi SD, Sen E (2016) CK2 inhibition induced PDK4–AMPK axis regulates metabolic adaptation and survival responses in glioma. Exp Cell Res 344:132–142. https://doi.org/10.1016/j.yexcr.2016.03.017

    Article  CAS  PubMed  Google Scholar 

  16. Sun Y et al (2012) Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells. Int J Radiat Oncol Biol Phys 82:e563-572. https://doi.org/10.1016/j.ijrobp.2011.06.1999

    Article  CAS  PubMed  Google Scholar 

  17. Brown AR et al (2015) Kruppel-like factor 9 (KLF9) prevents colorectal cancer through inhibition of interferon-related signaling. Carcinogenesis 36:946–955. https://doi.org/10.1093/carcin/bgv104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Korani M et al (2013) The evaluation of the FOXO1, KLF9 and YT521 genes expression in human endometrial cancer. Clin Lab 59:483–489

    Article  CAS  Google Scholar 

  19. Shen P et al (2014) KLF9, a transcription factor induced in flutamide-caused cell apoptosis, inhibits AKT activation and suppresses tumor growth of prostate cancer cells. Prostate 74:946–958. https://doi.org/10.1002/pros.22812

    Article  CAS  PubMed  Google Scholar 

  20. Wang A et al (2017) USP22 induces cisplatin resistance in lung adenocarcinoma by regulating gammaH2AX-mediated DNA damage repair and Ku70/Bax-mediated apoptosis. Front Pharmacol 8:274. https://doi.org/10.3389/fphar.2017.00274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Coughlin CT, Richmond RC (1989) Biologic and clinical developments of cisplatin combined with radiation: concepts, utility, projections for new trials, and the emergence of carboplatin. Semin Oncol 16:31–43

    CAS  PubMed  Google Scholar 

  22. Rowles J et al (1996) Cloning and characterization of PDK4 on 7q21.3 encoding a fourth pyruvate dehydrogenase kinase isoenzyme in human. J Biol Chem 271:22376–22382

    Article  CAS  Google Scholar 

  23. Liu Z et al (2014b) PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade. J Biol Chem 289:29739–29749. https://doi.org/10.1074/jbc.M114.584821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim MY et al (2015) ZBTB2 increases PDK4 expression by transcriptional repression of RelA/p65. Nucleic Acids Res 43:1609–1625. https://doi.org/10.1093/nar/gkv026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang Y et al (2014) The combinatory effects of PPAR-gamma agonist and survivin inhibition on the cancer stem-like phenotype and cell proliferation in bladder cancer cells. Int J Mol Med 34:262–268. https://doi.org/10.3892/ijmm.2014.1774

    Article  CAS  PubMed  Google Scholar 

  26. Bertout JA, Patel SA, Simon MC (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8:967–975. https://doi.org/10.1038/nrc2540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kontos CK et al (2017) mRNA overexpression of the hypoxia inducible factor 1 alpha subunit gene (HIF1A): an independent predictor of poor overall survival in chronic lymphocytic leukemia. Leuk Res 53:65–73. https://doi.org/10.1016/j.leukres.2016.11.014

    Article  CAS  PubMed  Google Scholar 

  28. Baba Y et al (2010) HIF1A overexpression is associated with poor prognosis in a cohort of 731 colorectal cancers. Am J Pathol 176:2292–2301. https://doi.org/10.2353/ajpath.2010.090972

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mohammed N et al (2011) EPAS1 mRNA in plasma from colorectal cancer patients is associated with poor outcome in advanced stages. Oncol Lett 2:719–724. https://doi.org/10.3892/ol.2011.294

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by Programs for Natural Science Basic Research Plan in Shaanxi Province of China, Grant/Award (No. 2017JQ8059); Key research and development projects of Shaanxi Province (No. 2018SF-071); Exploration and Innovation projects of first affiliated hospital of Xi'an Jiaotong University (No. 2019ZYTS-05).

Author information

Author notes

  1. Shuo Yu and Yang Li contributed equally.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710000, Shaanxi, China

    Shuo Yu, Yang Li, Hui Ren, Hong Zhou, Qian Ning, Xue Chen, Tinghua Hu & Lan Yang

  2. Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710000, Shaanxi, China

    Shuo Yu

Authors
  1. Shuo Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qian Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xue Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tinghua Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Tinghua Hu or Lan Yang.

Ethics declarations

Conflict of interest

All authors are aware of and agree to submit this manuscript. Every author declares that they have no conflicts of interest in the research.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yu, S., Li, Y., Ren, H. et al. PDK4 promotes tumorigenesis and cisplatin resistance in lung adenocarcinoma via transcriptional regulation of EPAS1. Cancer Chemother Pharmacol 87, 207–215 (2021). https://doi.org/10.1007/s00280-020-04188-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-020-04188-9

Keywords

Search

Navigation