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Combating trastuzumab resistance by targeting thioredoxin-1/PTEN interaction

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Tumor Biology

Abstract

Trastuzumab is by far the drug of choice for treatment of human epidermal growth factor receptor 2 (Her2) overexpressing breast cancer patients. However, frequently, the therapy remains ineffective due to the induced drug resistance. In spite of various reported mechanisms, we hypothesize that the acquired resistance to trastuzumab might be attributed to the failure of the drug to activate phosphatase and tensin homolog (PTEN) mainly due to the high level of reduced thioredoxin-1 protein among the resistant cells. In the present study, the effect(s) of PX-12, a Trx-1 inhibitor, was examined on proliferation of breast cancer cells which are unresponsive to trastuzumab. Treatment of the cells with PX-12 (5 μM) and trastuzumab (10 μg/ml) reduced cells viabilities, p-Akt, and Bcl2 levels while increasing the levels of reactive oxygen species (ROS) and p-JNK with consequent higher levels of G1 arrest and apoptosis among the resistant cells compared to parental trastuzumab sensitive cells. The most significant observation was that PX-12/trastuzumab co-treatment enhanced the cell membrane localization of PTEN which is believed to be the active biological form of the signal. Our data confirmed that Trx-1 inhibition is required for chemosensitization of resistant breast cancer cells to anti-Her2 therapy, and this approach might offer an alternative clinical strategy for preventing acquired resistance.

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References

  1. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CEJR, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84.

    Article  CAS  PubMed  Google Scholar 

  2. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–92.

    Article  CAS  PubMed  Google Scholar 

  3. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:719–26.

    Article  CAS  PubMed  Google Scholar 

  4. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26:1642–9.

    Article  CAS  PubMed  Google Scholar 

  5. De Laurentiis M, Cancello G, Zinno L, Montagna E, Malorni L, Esposito A, et al. Targeting HER2 as a therapeutic strategy for breast cancer: a paradigmatic shift of drug development in oncology. Ann Oncol. 2005;16:iv7–13.

    Article  PubMed  Google Scholar 

  6. Lan KH, Lu C, Yu D. Mechanisms of trastuzumab resistance and their clinical implications. Ann N Y Acad Sci. 2005;1059:70–5.

    Article  CAS  PubMed  Google Scholar 

  7. Piccart M. Circumventing de novo and acquired resistance to trastuzumab: new hope for the care of ErbB2-positive breast cancer. Clin Breast Cancer. 2008;8:S100–13.

    Article  CAS  PubMed  Google Scholar 

  8. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65:11118–28.

    Article  CAS  PubMed  Google Scholar 

  9. Nahta R, Takahashi T, Ueno NT, Hung MC, Esteva FJ. P27kip1 down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 2004;64:3981–6.

    Article  CAS  PubMed  Google Scholar 

  10. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117–27.

    Article  CAS  PubMed  Google Scholar 

  11. Parsons R, Simpson L. PTEN and cancer. Methods Mol Biol. 2003;222:147–66.

    CAS  PubMed  Google Scholar 

  12. Takei Y, Saga Y, Mizukami H, Takayama T, Ohwada M, Ozawa K, et al. Overexpression of PTEN in ovarian cancer cells suppresses ip dissemination and extends survival in mice. Mol Cancer Ther. 2008;7:704–11.

    Article  CAS  PubMed  Google Scholar 

  13. Squire JA. TMPRSS2-ERG and PTEN loss in prostate cancer. Nat Genet. 2009;41:509–10.

    Article  CAS  PubMed  Google Scholar 

  14. Seront E, Pinto A, Bouzin C, Bertrand L, Machiels JP, Feron O. PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation. Br J Cancer. 2013;109:1586–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lin PY, Fosmire SP, Park SH, Park JY, Baksh S, Modiano JF, et al. Attenuation of PTEN increases p21 stability and cytosolic localization in kidney cancer cells: a potential mechanism of apoptosis resistance. Mol Cancer. 2007;6:16.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–39.

    Article  CAS  PubMed  Google Scholar 

  17. Yang Y, Shao N, Luo G, Li L, Zheng L, Nilsson-Ehle P, et al. Mutations of PTEN gene in gliomas correlate to tumor differentiation and short-term survival rate. Anticancer Res. 2010;30:981–5.

    CAS  PubMed  Google Scholar 

  18. Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003;22:3113–22.

    Article  CAS  PubMed  Google Scholar 

  19. Liu KJL, Yin B, Zhang R, Zhang J, Li P, et al. Distinct roles for PTEN in prevention of T cell lymphoma and autoimmunity in mice. J Clin Invest. 2010;120:2497–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fulcher L, Friedrichs W, Grünwald V, Ray R, Hidalgo M. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann Oncol. 2004;15:1510–6.

    Article  PubMed  Google Scholar 

  21. Gu J, Tamura M, Pankov R, Danen EH, Takino T, Matsumoto K, et al. Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J Cell Biol. 1999;146:389–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Georgescu MM. PTEN tumor suppressor network in PI3K-Akt pathway control. Genes Cancer. 2010;1:1170–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Meuillet EJ, Mahadevan D, Berggren M, Coon A, Powis G. Thioredoxin-1 binds to the C2 domain of PTEN inhibiting PTEN’s lipid phosphatase activity and membrane binding: a mechanism for the functional loss of PTEN’s tumor suppressor activity. Arch Biochem Biophys. 2004;429:123–33.

    Article  CAS  PubMed  Google Scholar 

  24. Das KC, Das CK. Thioredoxin, a singlet oxygen quencher and hydroxyl radical scavenger: redox independent functions. Biochem Biophys Res Commun. 2000;277:443–7.

    Article  CAS  PubMed  Google Scholar 

  25. Powis G, Kirkpatrick DL. Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol. 2007;7(4):392–7.

    Article  CAS  PubMed  Google Scholar 

  26. Wangpaichitr M, Sullivan EJ, Theodoropoulos G, Wu C, You M, Feun LG, et al. The relationship of thioredoxin-1 and cisplatin resistance: its impact on ROS and oxidative metabolism in lung cancer cells. Mol Cancer Ther. 2012;11:604–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kim SJ, Miyoshi Y, Taguchi T, Tamaki Y, Nakamura H, Yodoi J, et al. High thioredoxin expression is associated with resistance to docetaxel in primary breast cancer. Clin Cancer Res. 2005;11:8425–30.

    Article  CAS  PubMed  Google Scholar 

  28. Lechner S, Müller-Ladner U, Neumann E, Spöttl T, Schlottmann K, Rüschoff J, et al. Thioredoxin reductase 1 expression in colon cancer: discrepancy between in vitro and in vivo findings. Lab Investig. 2003;83:1321–31.

    Article  CAS  PubMed  Google Scholar 

  29. Noda N, Ochiai A, Miyazaki K, Sugimura T, Terada M, Wakasugi H. Detection of thioredoxin in gastric cancer: association with histological type. Antioxid Redox Signal. 2000;2:519–28.

    Article  CAS  PubMed  Google Scholar 

  30. Welsh SJ, Williams RR, Birmingham A, Newman DJ, Kirkpatrick DL, Powis G. The thioredoxin redox inhibitors 1-methylpropyl 2-Imidazolyl disulfide and pleurotin inhibit hypoxia-induced factor 1α and vascular endothelial growth factor formation 1. Mol Cancer Ther. 2003;2:235–43.

    CAS  PubMed  Google Scholar 

  31. Tonissen KF, Di Trapani G. Thioredoxin system inhibitors as mediators of apoptosis for cancer therapy. Mol Nutr Food Res. 2009;53:87–103.

    Article  CAS  PubMed  Google Scholar 

  32. Lebel CP, Ischiropoulos H, Bondy SC. Evaluation of the probe 2′, 7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol. 1992;5:227–31.

    Article  CAS  PubMed  Google Scholar 

  33. Liu JL, Sheng X, Hortobagyi ZK, Mao Z, Gallick GE, Yung WA. Nuclear PTEN-mediated growth suppression is independent of Akt down-regulation. Mol Cell Biol. 2005;25:6211–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ. Trastuzumab-induced HER reprogramming in “resistant” breast carcinoma cells. Cancer Res. 2009;69:2191–4.

    Article  CAS  PubMed  Google Scholar 

  35. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007;318:287–90.

    Article  CAS  PubMed  Google Scholar 

  36. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.

    Article  CAS  PubMed  Google Scholar 

  37. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563–72.

    Article  CAS  PubMed  Google Scholar 

  38. Ravi D, Muniyappa H, Das KC. Endogenous thioredoxin is required for redox cycling of anthracyclines and p53-dependent apoptosis in cancer cells. J Biol Chem. 2005;280:40084–96.

    Article  CAS  PubMed  Google Scholar 

  39. Bloomfield KL, Osborne SA, Kennedy DD, Clarke FM, Tonissen KF. Thioredoxin-mediated redox control of the transcription factor Sp1 and regulation of the thioredoxin gene promoter. Gene. 2003;319:107–16.

    Article  CAS  PubMed  Google Scholar 

  40. Sakurai A, Yuasa K, Shoji Y, Himeno S, Tsujimoto M, Kunimoto M, et al. Overexpression of thioredoxin reductase 1 regulates NF‐κB activation. J Cell Physiol. 2004;198:22–30.

    Article  CAS  PubMed  Google Scholar 

  41. Wei SJ, Botero A, Hirota K, Bradbury CM, Markovina S, Laszlo A, et al. Thioredoxin nuclear translocation and interaction with redox factor-1 activates the activator protein-1 transcription factor in response to ionizing radiation. Cancer Res. 2000;60:6688–95.

    CAS  PubMed  Google Scholar 

  42. Naranjo-Suarez S, Carlson BA, Tobe R, Yoo MH, Tsuji PA, Gladyshev VN, et al. Regulation of HIF-1α activity by overexpression of thioredoxin is independent of thioredoxin reductase status. Mol Cells. 2013;36:151–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Manoharan R, Seong HA, Ha H. Thioredoxin inhibits MPK38-induced ASK1, TGF‐β, and p53 function in a phosphorylation-dependent manner. Free Radic Biol Med. 2013;63:313–24.

    Article  CAS  PubMed  Google Scholar 

  44. Schwertassek U, Haque A, Krishnan N, Greiner R, Weingarten L, et al. Reactivation of oxidized PTP1B and PTEN by thioredoxin 1. FEBS J. 2014;281:3545–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lee SR, Yang KS, Kwon J, Lee C, Jeong W, Rhee SG. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem. 2002;277:20336–42.

    Article  CAS  PubMed  Google Scholar 

  46. Kim YH, Coon A, Baker AF, Powis G. Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase. Cancer Chemother Pharmacol. 2011;68(2):405–13.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors appreciate the joint financial support of this investigation by the Research Council of University of Tehran and the Iranian National Science Foundation.

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  1. Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145–1384, Tehran, Iran

    Akram Sadeghirizi, Razieh Yazdanparast & Safiyeh Aghazadeh

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  1. Akram Sadeghirizi
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Correspondence to Razieh Yazdanparast.

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Sadeghirizi, A., Yazdanparast, R. & Aghazadeh, S. Combating trastuzumab resistance by targeting thioredoxin-1/PTEN interaction. Tumor Biol. 37, 6737–6747 (2016). https://doi.org/10.1007/s13277-015-4424-9

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  • DOI: https://doi.org/10.1007/s13277-015-4424-9

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