Article | Published:

Abrogation of glutathione peroxidase-1 drives EMT and chemoresistance in pancreatic cancer by activating ROS-mediated Akt/GSK3β/Snail signaling

Oncogene (2018) | Download Citation


The devastating prognosis of pancreatic ductal adenocarcinoma (PDAC) is partially attributed to chemotherapy resistance. Glutathione peroxidase-1 (GPx1) plays various roles in the development and progression of multiple tumors, with the exception of pancreatic cancer. Here, we tentatively explored the role of GPx1 in the malignant biological behavior and gemcitabine (GEM) resistance of PDAC. GPx1 levels were detected using tissue microarrays and were negatively correlated with the overall survival of patients with PDAC. GPx1 silencing induced a mesenchymal transition phenotype and increased GEM resistance in vitro and in vivo. Additionally, the activation of reactive oxygen species (ROS)-mediated Akt/glycogen synthase kinase 3β (GSK3β)/Snail signaling was involved in this process, as determined by RNA sequencing. Moreover, low GPx1 expression correlated with a worse survival rate in patients with PDAC who received GEM adjuvant chemotherapy, whereas this correlation was not detected in patients receiving fluoropyrimidine. Based on our results, GPx1 inhibits the epithelial–mesenchymal transition (EMT) and chemoresistance by regulating the Akt/GSK3β/Snail signaling axis in PDAC. Furthermore, GPx1 may be a potential predictive biomarker in GEM-treated PDAC patients.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.


  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

  2. 2.

    Midha S, Chawla S, Garg PK. Modifiable and non-modifiable risk factors for pancreatic cancer: a review. Cancer Lett. 2016;381:269–77.

  3. 3.

    Hoos WA, James PM, Rahib L, Talley AW, Fleshman JM, Matrisian LM. Pancreatic cancer clinical trials and accrual in the United States. J Clin Oncol. 2013;31:3432–8.

  4. 4.

    Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363:1049–57.

  5. 5.

    Flohe L, Gunzler WA, Schock HH. Glutathione peroxidase: a selenoenzyme. FEBS Lett. 1973;32:132–4.

  6. 6.

    Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973;179:588–90.

  7. 7.

    Szatrowski TP, Nathan CF. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 1991;51:794–8.

  8. 8.

    Storz P. Reactive oxygen species in tumor progression. Front Biosci. 2005;10:1881–96.

  9. 9.

    Faucher K, Rabinovitch-Chable H, Cook-Moreau J, Barriere G, Sturtz F, Rigaud M. Overexpression of human GPX1 modifies Bax to Bcl-2 apoptotic ratio in human endothelial cells. Mol Cell Biochem. 2005;277:81–7.

  10. 10.

    Li S, Yan T, Yang JQ, Oberley TD, Oberley LW. The role of cellular glutathione peroxidase redox regulation in the suppression of tumor cell growth by manganese superoxide dismutase. Cancer Res. 2000;60:3927–39.

  11. 11.

    Ravn-Haren G, Olsen A, Tjonneland A, Dragsted LO, Nexo BA, Wallin H, et al. Associations between GPX1 Pro198Leu polymorphism, erythrocyte GPX activity, alcohol consumption and breast cancer risk in a prospective cohort study. Carcinogenesis. 2006;27:820–5.

  12. 12.

    Ichimura Y, Habuchi T, Tsuchiya N, Wang L, Oyama C, Sato K, et al. Increased risk of bladder cancer associated with a glutathione peroxidase 1 codon 198 variant. J Urol. 2004;172:728–32.

  13. 13.

    Arsova-Sarafinovska Z, Matevska N, Eken A, Petrovski D, Banev S, Dzikova S, et al. Glutathione peroxidase 1 (GPX1) genetic polymorphism, erythrocyte GPX activity, and prostate cancer risk. Int Urol Nephrol. 2009;41:63–70.

  14. 14.

    Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.

  15. 15.

    Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973–81.

  16. 16.

    Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA. 2010;107:15449–54.

  17. 17.

    Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012;22:725–36.

  18. 18.

    Hiscox S, Jiang WG, Obermeier K, Taylor K, Morgan L, Burmi R, et al. Tamoxifen resistance in MCF7 cells promotes EMT-like behaviour and involves modulation of beta-catenin phosphorylation. Int J Cancer. 2006;118:290–301.

  19. 19.

    Hiscox S, Morgan L, Barrow D, Dutkowskil C, Wakeling A, Nicholson RI. Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib (‘Iressa’, ZD1839). Clin Exp Metastas. 2004;21:201–12.

  20. 20.

    Yang AD, Fan F, Camp ER, van Buren G, Liu W, Somcio R, et al. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006;12:4147–53.

  21. 21.

    Rho JK, Choi YJ, Lee JK, Ryoo BY, Na II, Yang SH, et al. Epithelial to mesenchymal transition derived from repeated exposure to gefitinib determines the sensitivity to EGFR inhibitors in A549, a non-small cell lung cancer cell line. Lung Cancer. 2009;63:219–26.

  22. 22.

    Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525–30.

  23. 23.

    Peinado H, Quintanilla M, Cano A. Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. J Biol Chem. 2003;278:21113–23.

  24. 24.

    Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004;6:931–40.

  25. 25.

    Kourie HR, Gharios J, Elkarak F, Antoun J, Ghosn M. Is metastatic pancreatic cancer an untargetable malignancy? World J Gastrointest Oncol. 2016;8:297–304.

  26. 26.

    Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691–703.

  27. 27.

    Gao X, Schottker B. Reduction-oxidation pathways involved in cancer development: a systematic review of literature reviews. Oncotarget. 2017;8:51888–906.

  28. 28.

    Brigelius-Flohe R, Kipp A. Glutathione peroxidases in different stages of carcinogenesis. Biochim Biophys Acta. 2009;1790:1555–68.

  29. 29.

    Ratnasinghe D, Tangrea JA, Andersen MR, Barrett MJ, Virtamo J, Taylor PR, et al. Glutathione peroxidase codon 198 polymorphism variant increases lung cancer risk. Cancer Res. 2000;60:6381–3.

  30. 30.

    Kodydkova J, Vavrova L, Stankova B, Macasek J, Krechler T, Zak A. Antioxidant status and oxidative stress markers in pancreatic cancer and chronic pancreatitis. Pancreas. 2013;42:614–21.

  31. 31.

    Ponti D, Zaffaroni N, Capelli C, Daidone MG. Breast cancer stem cells: an overview. Eur J Cancer. 2006;42:1219–24.

  32. 32.

    Soltysova A, Altanerova V, Altaner C. Cancer stem cells. Neoplasma. 2005;52:435–40.

  33. 33.

    Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3:155–66.

  34. 34.

    Vega S, Morales AV, Ocana OH, Valdes F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 2004;18:1131–43.

  35. 35.

    Zhu LF, Hu Y, Yang CC, Xu XH, Ning TY, Wang ZL, et al. Snail overexpression induces an epithelial to mesenchymal transition and cancer stem cell-like properties in SCC9 cells. Lab Investig. 2012;92:744–52.

  36. 36.

    Marechal R, Bachet JB, Mackey JR, Dalban C, Demetter P, Graham K, et al. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology. 2012;143:664–74.e6.

  37. 37.

    Namba T, Kodama R, Moritomo S, Hoshino T, Mizushima T. Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3beta-Snail pathway. Cell Death Dis. 2015;6:e1795.

  38. 38.

    Kulak MV, Cyr AR, Woodfield GW, Bogachek M, Spanheimer PM, Li T, et al. Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer. Oncogene. 2013;32:4043–51.

  39. 39.

    Xiong G, Huang H, Feng M, Yang G, Zheng S, You L, et al. MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma. J Exp Clin Cancer Res. 2018;37:76.

  40. 40.

    Maseki S, Ijichi K, Tanaka H, Fujii M, Hasegawa Y, Ogawa T, et al. Acquisition of EMT phenotype in the gefitinib-resistant cells of a head and neck squamous cell carcinoma cell line through Akt/GSK-3beta/snail signalling pathway. Br J Cancer. 2012;106:1196–204.

  41. 41.

    Miething C, Scuoppo C, Bosbach B, Appelmann I, Nakitandwe J, Ma J, et al. PTEN action in leukaemia dictated by the tissue microenvironment. Nature. 2014;510:402–6.

  42. 42.

    Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S, et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature. 2004;428:332–7.

  43. 43.

    Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010;9:1956–67.

  44. 44.

    Cullen JJ, Mitros FA, Oberley LW. Expression of antioxidant enzymes in diseases of the human pancreas: another link between chronic pancreatitis and pancreatic cancer. Pancreas. 2003;26:23–27.

  45. 45.

    Sun S, Xie F, Zhang Q, Cui Z, Cheng X, Zhong F, et al. Advanced oxidation protein products induce hepatocyte epithelial-mesenchymal transition via a ROS-dependent, TGF-beta/Smad signaling pathway. Cell Biol Int. 2017;41:842–53.

  46. 46.

    Chao W, Deng JS, Li PY, Liang YC, Huang GJ. 3,4-Dihydroxybenzalactone suppresses human non-small cell lung carcinoma cells metastasis via suppression of epithelial to mesenchymal transition, ROS-mediated PI3K/AKT/MAPK/MMP and NFkappaB signaling pathways. Molecules. 2017;22:E537.

  47. 47.

    Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310:1473–81.

  48. 48.

    Ji S, Qin Y, Liang C, Huang R, Shi S, Liu J, et al. FBW7 (F-box and WD repeat domain-containing 7) negatively regulates glucose metabolism by targeting the c-Myc/TXNIP (thioredoxin-binding protein) axis in pancreatic cancer. Clin Cancer Res. 2016;22:3950–60.

  49. 49.

    Liang C, Yu XJ, Guo XZ, Sun MH, Wang Z, Song Y, et al. MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine. Oncotarget. 2015;6:14440–55.

  50. 50.

    Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008;5:621–8.

Download references


We thank Professor Daming Gao (Institutes for Biological Sciences, Chinese Academy of Sciences) and Professor Yi Qin (Cancer Research Institute, Fudan University) for providing critical comments. This study was supported by grants from the National Science Foundation for Distinguished Young Scholars of China (no. 81625016) and the Shanghai Sailing Program (no. 17YF1402500).

Author information

Author notes


    1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

      • Qingcai Meng
      • , Si Shi
      • , Chen Liang
      • , Dingkong Liang
      • , Jie Hua
      • , Bo Zhang
      • , Jin Xu
      •  & Xianjun Yu
    2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

      • Qingcai Meng
      • , Si Shi
      • , Chen Liang
      • , Dingkong Liang
      • , Jie Hua
      • , Bo Zhang
      • , Jin Xu
      •  & Xianjun Yu
    3. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China

      • Qingcai Meng
      • , Si Shi
      • , Chen Liang
      • , Dingkong Liang
      • , Jie Hua
      • , Bo Zhang
      • , Jin Xu
      •  & Xianjun Yu
    4. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China

      • Qingcai Meng
      • , Si Shi
      • , Chen Liang
      • , Dingkong Liang
      • , Jie Hua
      • , Bo Zhang
      • , Jin Xu
      •  & Xianjun Yu


    1. Search for Qingcai Meng in:

    2. Search for Si Shi in:

    3. Search for Chen Liang in:

    4. Search for Dingkong Liang in:

    5. Search for Jie Hua in:

    6. Search for Bo Zhang in:

    7. Search for Jin Xu in:

    8. Search for Xianjun Yu in:

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Corresponding author

    Correspondence to Xianjun Yu.

    Electronic supplementary material

    About this article

    Publication history