Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Cellular and Molecular Biology

Targeting epidermal growth factor receptor in paclitaxel-resistant human breast and lung cancer cells with upregulated glucose-6-phosphate dehydrogenase

British Journal of Cancer volume 127, pages 661–674 (2022)Cite this article

Subjects

Abstract

Background

Chemoresistance is a major obstacle to the successful treatment of triple-negative breast cancer (TNBC) and non-small-cell lung cancer (NSCLC). Therapeutic strategies to overcome chemoresistance are necessary to improve the prognosis of patients with these cancers.

Methods

Paclitaxel-resistant TNBC and NSCLC sublines were generated through continuous paclitaxel treatment over 6 months. The mechanistic investigation was conducted using MTT assay, LC/MS-based metabolite analysis, flow cytometry, western blot analysis, real-time PCR and tumour xenograft experiments.

Results

Glucose-6-phosphate dehydrogenase (G6PD) expression along with an increase in 3-phosphoglycerates and ribulose-5-phosphate production was upregulated in paclitaxel-resistant cells. Blockade of G6PD decreased viability of paclitaxel-resistant cells in vitro and the growth of paclitaxel-resistant MDA/R xenograft tumours in vivo. Mechanistically, activation of the epidermal growth factor receptor (EGFR)/Akt pathway mediates G6PD expression and G6PD-induced cell survival. Blockade of the EGFR pathway inhibited G6PD expression and sensitised those paclitaxel-resistant cells to paclitaxel treatment in vitro and in vivo. Analysis of publicly available datasets revealed an association between G6PD and unfavourable clinical outcomes in patients with breast or lung cancer.

Conclusions

EGFR signaling-mediated G6PD expression plays a pivotal role in paclitaxel resistance, highlighting the potential of targeting EGFR to overcome paclitaxel resistance in TNBC and NSCLC cells overexpressing G6PD.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Establishment of paclitaxel-resistant cells.
Fig. 2: Characteristics of paclitaxel-resistant cells.
Fig. 3: Inhibition of cell viability and colony formation and induction of apoptosis in paclitaxel-resistant cells by treatment with 2-DG.
Fig. 4: Upregulation of glucose uptake and cellular ROS but downregulation of basal mitochondrial respiration and glycolysis in paclitaxel-resistant cells.
Fig. 5: Upregulation of G6PD in paclitaxel-resistant cells.
Fig. 6: Activation of the EGFR/Akt pathway in paclitaxel-resistant cells.

Similar content being viewed by others

Data availability

All data generated or analysed during this study are included in this published article.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  PubMed  Google Scholar 

  2. Jung KW, Won YJ, Hong S, Kong HJ, Im JS, Seo HG. Prediction of cancer incidence and mortality in Korea, 2021. Cancer Res Treat. 2021;53:316–22.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Gridelli C, Rossi A, Carbone DP, Guarize J, Karachaliou N, Mok T, et al. Non-small-cell lung cancer. Nat Rev Dis Prim. 2015;1:15009.

    Article  PubMed  Google Scholar 

  4. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Prim. 2019;5:66.

    Article  PubMed  Google Scholar 

  5. Jones GB. History of Anticancer Drugs. eLS. 2014. https://doi.org/10.1002/9780470015902.a0003630.pub2.

  6. Lee YT, Tan YJ, Oon CE. Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol. 2018;834:188–96.

    Article  CAS  PubMed  Google Scholar 

  7. Maeda H, Khatami M. Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs. Clin Transl Med. 2018;7:11.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575:299–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Abu Samaan TM, Samec M, Liskova A, Kubatka P, Busselberg D. Paclitaxel’s mechanistic and clinical effects on breast cancer. Biomolecules. 2019;9:789.

    Article  CAS  PubMed Central  Google Scholar 

  10. Min HY, Lee HY. Mechanisms of resistance to chemotherapy in non-small cell lung cancer. Arch Pharm Res. 2021;44:146–64.

    Article  CAS  PubMed  Google Scholar 

  11. Guo W, Tan HY, Chen F, Wang N, Feng Y. Targeting cancer metabolism to resensitize chemotherapy: potential development of cancer chemosensitizers from traditional Chinese medicines. Cancers (Basel). 2020;12:404.

    Article  CAS  Google Scholar 

  12. Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10:267–77.

    Article  CAS  PubMed  Google Scholar 

  13. Vander Heiden MG, DeBerardinis RJ. Understanding the intersections between metabolism and cancer biology. Cell. 2017;168:657–69.

    Article  PubMed Central  CAS  Google Scholar 

  14. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    Article  CAS  Google Scholar 

  15. Cho ES, Cha YH, Kim HS, Kim NH, Yook JI. The pentose phosphate pathway as a potential target for cancer therapy. Biomol Ther (Seoul). 2018;26:29–38.

    Article  CAS  Google Scholar 

  16. Patra KC, Hay N. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014;39:347–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yang HC, Wu YH, Yen WC, Liu HY, Hwang TL, Stern A, et al. The redox role of G6PD in cell growth, cell death, and cancer. Cells. 2019;8:1055.

    Article  CAS  PubMed Central  Google Scholar 

  18. Giacomini I, Ragazzi E, Pasut G, Montopoli M. The pentose phosphate pathway and its involvement in cisplatin resistance. Int J Mol Sci. 2020;21:937.

    Article  CAS  PubMed Central  Google Scholar 

  19. Kim WY, Prudkin L, Feng L, Kim ES, Hennessy B, Lee JS, et al. Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors. Cancer. 2012;118:3993–4003.

    Article  CAS  PubMed  Google Scholar 

  20. Perdomo JA, Naomoto Y, Haisa M, Fujiwara T, Hamada M, Yasuoka Y, et al. In vivo influence of p53 status on proliferation and chemoradiosensitivity in non-small-cell lung cancer. J Cancer Res Clin Oncol. 1998;124:10–18.

    Article  CAS  PubMed  Google Scholar 

  21. Hyun SY, Le HT, Min HY, Pei H, Lim Y, Song I, et al. Evodiamine inhibits both stem cell and non-stem-cell populations in human cancer cells by targeting heat shock protein 70. Theranostics. 2021;11:2932–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jiang P, Du W, Wang X, Mancuso A, Gao X, Wu M, et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol. 2011;13:310–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(T)(-Delta Delta C) method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  24. Kim JH, Nam B, Choi YJ, Kim SY, Lee J-E, Sung KJ, et al. Enhanced glycolysis supports cell survival in EGFR-mutant lung adenocarcinoma by inhibiting autophagy-mediated EGFR degradation. Cancer Res. 2018;78:4482–96.

    Article  CAS  PubMed  Google Scholar 

  25. Amelio I, Gostev M, Knight RA, Willis AE, Melino G, Antonov AV. DRUGSURV: a resource for repositioning of approved and experimental drugs in oncology based on patient survival information. Cell Death Dis. 2014;5:e1051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhou HM, Zhang JG, Zhang X, Li Q. Targeting cancer stem cells for reversing therapy resistance: mechanism, signaling, and prospective agents. Signal Transduct Target Ther. 2021;6:62.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yang L, Shi P, Zhao G, Xu J, Peng W, Zhang J, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther. 2020;5:8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Liang CC, Park AY, Guan JL. In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc. 2007;2:329–33.

    Article  CAS  PubMed  Google Scholar 

  29. Justus CR, Leffler N, Ruiz-Echevarria M, Yang LV. In vitro cell migration and invasion assays. J Vis Exp. 2014. https://doi.org/10.3791/51046.

  30. Zaal EA, Berkers CR. The influence of metabolism on drug response in cancer. Front Oncol. 2018;8:500.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lyssiotis CA, Kimmelman AC. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 2017;27:863–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pajak B, Siwiak E, Soltyka M, Priebe A, Zielinski R, Fokt I, et al. 2-deoxy-d-glucose and its analogs: from diagnostic to therapeutic agents. Int J Mol Sci. 2019;21:234.

    Article  PubMed Central  CAS  Google Scholar 

  33. Zou C, Wang Y, Shen Z. 2-NBDG as a fluorescent indicator for direct glucose uptake measurement. J Biochem Biophys Methods. 2005;64:207–15.

    Article  CAS  PubMed  Google Scholar 

  34. Panieri E, Santoro MM. ROS homeostasis and metabolism: a dangerous liason in cancer cells. Cell Death Dis. 2016;7:e2253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ahsan H, Halpern J, Kibriya MG, Pierce BL, Tong L, Gamazon E, et al. A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age. Cancer Epidemiol Biomark Prev. 2014;23:658–69.

    Article  CAS  Google Scholar 

  36. Lee SY, Jin CC, Choi JE, Hong MJ, Jung DK, Do SK, et al. Genetic polymorphisms in glycolytic pathway are associated with the prognosis of patients with early stage non-small cell lung cancer. Sci Rep. 2016;6:35603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kohler E, Barrach H, Neubert D. Inhibition of NADP dependent oxidoreductases by the 6-aminonicotinamide analogue of NADP. FEBS Lett. 1970;6:225–8.

    Article  CAS  PubMed  Google Scholar 

  38. Tang PA, Tsao MS, Moore MJ. A review of erlotinib and its clinical use. Expert Opin Pharmacother. 2006;7:177–93.

    Article  CAS  PubMed  Google Scholar 

  39. Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy. Int J Mol Sci. 2020;21:3233.

    Article  CAS  PubMed Central  Google Scholar 

  40. Socinski MA. Single-agent paclitaxel in the treatment of advanced non-small cell lung cancer. Oncologist. 1999;4:408–16.

    Article  CAS  PubMed  Google Scholar 

  41. Perez EA. Paclitaxel in breast cancer. Oncologist. 1998;3:373–89.

    Article  CAS  PubMed  Google Scholar 

  42. Yang Q, Huang J, Wu Q, Cai Y, Zhu L, Lu X, et al. Acquisition of epithelial-mesenchymal transition is associated with Skp2 expression in paclitaxel-resistant breast cancer cells. Br J Cancer. 2014;110:1958–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wei-Hua W, Ning Z, Qian C, Dao-Wen J. ZIC2 promotes cancer stem cell traits via up-regulating OCT4 expression in lung adenocarcinoma cells. J Cancer. 2020;11:6070–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Li CY, Miao KL, Chen Y, Liu LY, Zhao GB, Lin MH, et al. Jagged2 promotes cancer stem cell properties of triple negative breast cancer cells and paclitaxel resistance via regulating microRNA-200. Eur Rev Med Pharmacol Sci. 2018;22:6008–14.

    PubMed  Google Scholar 

  45. van der Valk J, Bieback K, Buta C, Cochrane B, Dirks WG, Fu J, et al. Fetal bovine serum (FBS): past - present - future. ALTEX. 2018;35:99–118.

    Article  PubMed  Google Scholar 

  46. Grasmann G, Mondal A, Leithner K. Flexibility and adaptation of cancer cells in a heterogenous metabolic microenvironment. Int J Mol Sci. 2021;22:1476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhou M, Zhao Y, Ding Y, Liu H, Liu Z, Fodstad O, et al. Warburg effect in chemosensitivity: targeting lactate dehydrogenase-A re-sensitizes taxol-resistant cancer cells to taxol. Mol Cancer. 2010;9:33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016;16:650–62.

    Article  CAS  PubMed  Google Scholar 

  49. Lieberthal W, Triaca V, Koh JS, Pagano PJ, Levine JS. Role of superoxide in apoptosis induced by growth factor withdrawal. Am J Physiol. 1998;275:F691–702.

    CAS  PubMed  Google Scholar 

  50. Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G, et al. ROS in cancer therapy: the bright side of the moon. Exp Mol Med. 2020;52:192–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Varbiro G, Veres B, Gallyas F Jr, Sumegi B. Direct effect of Taxol on free radical formation and mitochondrial permeability transition. Free Radic Biol Med. 2001;31:548–58.

    Article  CAS  PubMed  Google Scholar 

  52. Sharma N, Bhushan A, He J, Kaushal G, Bhardwaj V. Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase. Cancer Metab. 2020;8:19.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ju HQ, Lin JF, Tian T, Xie D, Xu RH. NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications. Signal Transduct Target Ther. 2020;5:231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Dong T, Kang X, Liu Z, Zhao S, Ma W, Xuan Q, et al. Altered glycometabolism affects both clinical features and prognosis of triple-negative and neoadjuvant chemotherapy-treated breast cancer. Tumour Biol. 2016;37:8159–68.

    Article  CAS  PubMed  Google Scholar 

  55. Benito A, Polat IH, Noe V, Ciudad CJ, Marin S, Cascante M. Glucose-6-phosphate dehydrogenase and transketolase modulate breast cancer cell metabolic reprogramming and correlate with poor patient outcome. Oncotarget. 2017;8:106693–706.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Feng Q, Li X, Sun W, Sun M, Li Z, Sheng H, et al. Targeting G6PD reverses paclitaxel resistance in ovarian cancer by suppressing GSTP1. Biochem Pharmacol. 2020;178:114092.

    Article  CAS  PubMed  Google Scholar 

  57. Nagashio R, Oikawa S, Yanagita K, Hagiuda D, Kuchitsu Y, Igawa S, et al. Prognostic significance of G6PD expression and localization in lung adenocarcinoma. Biochim Biophys Acta Proteins Proteom. 2019;1867:38–46.

    Article  CAS  PubMed  Google Scholar 

  58. Ma X, Wang L, Huang, Li Y, Yang D, Li T, et al. Polo-like kinase 1 coordinates biosynthesis during cell cycle progression by directly activating pentose phosphate pathway. Nat Commun. 2017;8:1506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Pan S, World CJ, Kovacs CJ, Berk BC. Glucose 6-phosphate dehydrogenase is regulated through c-Src-mediated tyrosine phosphorylation in endothelial cells. Arterioscler Thromb Vasc Biol. 2009;29:895–901.

    Article  CAS  PubMed  Google Scholar 

  60. Rao X, Duan X, Mao W, Li X, Li Z, Li Q, et al. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth. Nat Commun. 2015;6:8468.

    Article  CAS  PubMed  Google Scholar 

  61. Lv Y, Cang W, Li Q, Liao X, Zhan M, Deng H, et al. Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRbeta-IL-6 axis in MUC1-positive cervical cancer. Oncogenesis. 2019;8:70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Aldonza MBD, Ku J, Hong JY, Kim D, Yu SJ, Lee MS, et al. Prior acquired resistance to paclitaxel relays diverse EGFR-targeted therapy persistence mechanisms. Sci Adv. 2020;6:eaav7416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23:5892–9.

    Article  CAS  PubMed  Google Scholar 

  64. Schuler M, Yang JC, Park K, Kim JH, Bennouna J, Chen YM, et al. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016;27:417–23.

    Article  CAS  PubMed  Google Scholar 

  65. Nakai K, Hung MC, Yamaguchi H. A perspective on anti-EGFR therapies targeting triple-negative breast cancer. Am J Cancer Res. 2016;6:1609–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14:611–29.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Coban B, Bergonzini C, Zweemer AJM, Danen EHJ. Metastasis: crosstalk between tissue mechanics and tumour cell plasticity. Br J Cancer. 2021;124:49–57.

    Article  PubMed  Google Scholar 

  68. Kim J, DeBerardinis RJ. Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 2019;30:434–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

This study was funded by the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1520250) and the National Research Foundation of Korea (NRF), the Ministry of Science and ICT (MSIT), Republic of Korea (NRF-2016R1A3B1908631).

Author information

Author notes

  1. These authors contributed equally: Hye-Young Min, Ho Jin Lee, Young-Ah Suh.

Authors and Affiliations

  1. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea

    Hye-Young Min, Ho Jin Lee, Honglan Pei, Hyukjin Kwon, Hyun-Ji Jang, Hye Jeong Yun & Ho-Young Lee

  2. Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Young-Ah Suh

  3. Department of Surgery, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Hyeong-Gon Moon

Authors
  1. Hye-Young Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ho Jin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Young-Ah Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Honglan Pei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyukjin Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hyun-Ji Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hye Jeong Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hyeong-Gon Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ho-Young Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HYM, HJL, HP, HK, HJJ and HJY performed in vitro experiments. HJL and HP performed in vivo experiments. HYM and YAS wrote the initial draft of the manuscript. HGM contributed to funding acquisition. HYL designed and supervised the study and wrote the manuscript.

Corresponding author

Correspondence to Ho-Young Lee.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All animal procedures were performed according to protocols approved by the Seoul National University Institutional Animal Care and Use Committee.

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.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Min, HY., Lee, H.J., Suh, YA. et al. Targeting epidermal growth factor receptor in paclitaxel-resistant human breast and lung cancer cells with upregulated glucose-6-phosphate dehydrogenase. Br J Cancer 127, 661–674 (2022). https://doi.org/10.1038/s41416-022-01843-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-01843-1

This article is cited by

Search

Advanced search

Quick links