Skip to main content

Advertisement

SpringerLink
Log in

Binding of Intracellular Myeloperoxidase to αV/β1 Integrin Serves as a Mechanism of Survival in Epithelial Ovarian Cancer

  • Gynecologic Oncology: Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

We were the first to report that epithelial ovarian cancer (EOC) cells and tissues express myeloperoxidase (MPO) that is known to play a role in immune surveillance and inflammation by myeloid cells. Additionally, we reported that MPO is colocalized with inducible nitric oxide synthase (iNOS), a key pro-oxidant enzyme, and plays a key role in regulating apoptosis in EOC cells. Whereas myeloid cells express MPO in a dimeric form, intriguingly, here we report the unique expression of only the monomeric form of MPO in EOC cells, tissues, and blood of an ovarian cancer patient. Additionally, we have identified a cell membrane receptor, αV/β1 integrin, that is uniquely expressed by both chemosensitive and chemoresistant EOC cells with significantly higher expression in chemoresistant EOC cells. More importantly, we have demonstrated that monoclonal antibodies against αV/β1 integrin induced cytotoxicity in EOC cells, but not in normal cells, that is also synergistic with conventional chemotherapies. Cytotoxicity of αV/β1 antibodies is due to conformational changes in αV/β1 integrin which prevents monomeric MPO binding to αV/β1 integrin inhibiting the activation of MPO, leading to increased apoptosis. Since normal epithelial cells and macrophages lack monomeric MPO and αV/β1 integrin system, targeting this unique MPO-dependent survival mechanism will selectively eliminate EOC cells and will be the target for developing specific ovarian cancer therapies.

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
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

All data to support claims comply with field standards.

Code Availability

Not applicable.

References

  1. Zand B, Coleman RL, Sood AK. Targeting angiogenesis in gynecologic cancers. Hematol Oncol Clin North Am. 2012;26:543–63. https://doi.org/10.1016/j.hoc.2012.01.009.

    Article  Google Scholar 

  2. J.S. Berek, R.C. Bast Jr, Epithelial ovarian cancer, BC Deck., 2003.

  3. Jelovac D, Armstrong DK. Recent progress in the diagnosis and treatment of ovarian cancer. CA A Cancer J for Clin. 2011;61:183–203. https://doi.org/10.3322/caac.20113.

    Article  Google Scholar 

  4. Matsuo K, Eno ML, Im DD, Rosenshein NB, Sood AK. Clinical relevance of extent of extreme drug resistance in epithelial ovarian carcinoma. Gynecol Oncol. 2010;116:61–5. https://doi.org/10.1016/j.ygyno.2009.09.018.

    Article  CAS  Google Scholar 

  5. Aoudjit F, Vuori K. Integrin signaling in cancer cell survival and chemoresistance. Chemother Res Pract. 2012;2012: 283181. https://doi.org/10.1155/2012/283181.

    Article  CAS  Google Scholar 

  6. Naci D, Vuori K, Aoudjit F. Alpha2beta1 integrin in cancer development and chemoresistance. Semin Cancer Biol. 2015;35:145–53. https://doi.org/10.1016/j.semcancer.2015.08.004.

    Article  CAS  Google Scholar 

  7. Saed GM, Fletcher NM, Diamond MP, Morris RT, Gomez-Lopez N, Memaj I. Novel expression of CD11b in epithelial ovarian cancer: potential therapeutic target. Gynecol Oncol. 2018;148:567–75. https://doi.org/10.1016/j.ygyno.2017.12.018.

    Article  CAS  Google Scholar 

  8. Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10:9–22. https://doi.org/10.1038/nrc2748.

    Article  CAS  Google Scholar 

  9. Liu Z, Wang F, Chen X. Integrin αvβ3-targeted cancer therapy. Drug Dev Res. 2008;69:329–39. https://doi.org/10.1002/ddr.20265.

    Article  CAS  Google Scholar 

  10. Blandin A-F, Renner G, Lehmann M, Lelong-Rebel I, Martin S, Dontenwill M. β1 integrins as therapeutic targets to disrupt hallmarks of cancer. Front Pharmacol. 2015;6:279. https://doi.org/10.3389/fphar.2015.00279.

    Article  CAS  Google Scholar 

  11. M. Kobayashi, K. Sawada, T. Kimura, Potential of integrin inhibitors for treating ovarian cancer: a lit. rev., Cancers . 9 (2017). https://doi.org/10.3390/cancers9070083.

  12. Lengyel E. Ovarian cancer development and metastasis. Am J Pathol. 2010;177:1053–64. https://doi.org/10.2353/ajpath.2010.100105.

    Article  Google Scholar 

  13. Maubant S, Cruet-Hennequart S, Dutoit S, Denoux Y, Crouet H, Henry-Amar M, Gauduchon P. Expression of α V-associated integrin β subunits in epithelial ovarian cancer and its relation to prognosis in patients treated with platinum-based regimens. J Mol Histol. 2005;36:119–29. https://doi.org/10.1007/s10735-004-4273-0.

    Article  CAS  Google Scholar 

  14. Cannistra SA, Ottensmeier C, Niloff J, Orta B, DiCarlo J. Expression and function of beta 1 and alpha v beta 3 integrins in ovarian cancer. Gynecol Oncol. 1995;58:216–25. https://doi.org/10.1006/gyno.1995.1214.

    Article  CAS  Google Scholar 

  15. Weidle UH, Birzele F. G. Kollmorgen, R. Rueger, Mechanisms and targets involved in dissemination of ovarian cancer. Cancer Genom Proteom. 2016;13:407–23. https://doi.org/10.21873/cgp.20004.

    Article  CAS  Google Scholar 

  16. Ahmed N, Pansino F, Clyde R, Murthi P, Quinn MA, Rice GE, Agrez MV, Mok S, Baker MS. Overexpression of alpha(v)beta6 integrin in serous epithelial ovarian cancer regulates extracellular matrix degradation via the plasminogen activation cascade. Carcinogen. 2002;23:237–44. https://doi.org/10.1093/carcin/23.2.237.

    Article  CAS  Google Scholar 

  17. van der Horst G, Bos L, van der Mark M, Cheung H, Heckmann B, Clément-Lacroix P, Lorenzon G, Pelger RCM, Bevers RFM, van der Pluijm G. Targeting of alpha-v integrins reduces malignancy of bladder carcinoma. PLoS ONE. 2014;9: e108464. https://doi.org/10.1371/journal.pone.0108464.

    Article  CAS  Google Scholar 

  18. Lee Y-C, Jin J-K, Cheng C-J, Huang C-F, Song JH, Huang M, Brown WS, Zhang S, Yu-Lee L-Y, Yeh ET, McIntyre BW, Logothetis CJ, Gallick GE, Lin S-H. Targeting constitutively activated β1 integrins inhibits prostate cancer metastasis. Mol Cancer Res. 2013;11:405–17. https://doi.org/10.1158/1541-7786.MCR-12-0551.

    Article  CAS  Google Scholar 

  19. Rae JM, Creighton CJ, Meck JM, Haddad BR, Johnson MD. MDA-MB-435 cells are derived from M14 melanoma cells––a loss for breast cancer, but a boon for melanoma research. Breast Cancer Res and Treat. 2007;104:13–9. https://doi.org/10.1007/s10549-006-9392-8.

    Article  Google Scholar 

  20. Bednarczyk M, Stege H, Grabbe S, Bros M. β2 integrins—multi-functional leukocyte receptors in health and disease. Int J of Mol Sci. 2020;21:1402. https://doi.org/10.3390/ijms21041402.

    Article  CAS  Google Scholar 

  21. Lau D, Mollnau H, Eiserich JP, Freeman BA, Daiber A, Gehling UM, Brümmer J, Rudolph V, Münzel T, Heitzer T, Meinertz T, Baldus S. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins. Proc Natl Acad Sci U S A. 2005;102:431–6. https://doi.org/10.1073/pnas.0405193102.

    Article  CAS  Google Scholar 

  22. Saed GM, Ali-Fehmi R, Jiang ZL, Fletcher NM, Diamond MP, Abu-Soud HM, Munkarah AR. Myeloperoxidase serves as a redox switch that regulates apoptosis in epithelial ovarian cancer. Gynecol Oncol. 2010;116:276–81. https://doi.org/10.1016/j.ygyno.2009.11.004.

    Article  CAS  Google Scholar 

  23. Fletcher NM, Jiang Z, Ali-Fehmi R, Levin NK, Belotte J, Tainsky MA, Diamond MP, Abu-Soud HM, Saed GM. Myeloperoxidase and free iron levels: potential biomarkers for early detection and prognosis of ovarian cancer. Cancer Biomark. 2011;10:267–75. https://doi.org/10.3233/CBM-2012-0255.

    Article  CAS  Google Scholar 

  24. Castillo-Tong DC, Pils D, Heinze G, Braicu I, Sehouli J, Reinthaller A, Schuster E, Wolf A, Watrowski R, Maki RA, Zeillinger R, Reynolds WF. Association of myeloperoxidase with ovarian cancer. Tumor Biol. 2014;35:141–8. https://doi.org/10.1007/s13277-013-1017-3.

    Article  CAS  Google Scholar 

  25. Abu-Soud HM, Hazen SL. Nitric oxide modulates the catalytic activity of myeloperoxidase. J Biol Chem. 2000;275:5425–30. https://doi.org/10.1074/jbc.275.8.5425.

    Article  CAS  Google Scholar 

  26. Wang J, Zhou J-Y, Zhang L, Wu GS. Involvement of MKP-1 and Bcl-2 in acquired cisplatin resistance in ovarian cancer cells. Cell Cycle. 2009;8:3191–8. https://doi.org/10.4161/cc.8.19.9751.

    Article  CAS  Google Scholar 

  27. A. Bellucci, C. Fiorentini, M. Zaltieri, C. Missale, P. Spano,2014 The “in situ” proximity ligation assay to probe protein–protein interactions in intact tissues, Methods in Mol. Biol. 397–405. https://doi.org/10.1007/978-1-4939-0944-5_27.

  28. Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nat. 2008;456:809–13. https://doi.org/10.1038/nature07424.

    Article  CAS  Google Scholar 

  29. Fanning J, Biddle WC, Goldrosen M, Crickard K, Crickard U, Piver MS, Foon KA. Comparison of cisplatin and carboplatin cytotoxicity in human ovarian cancer cell lines using the MTT assay. Gynecol Oncol. 1990;39:119–22. https://doi.org/10.1016/0090-8258(90)90416-i.

    Article  CAS  Google Scholar 

  30. Fletcher NM, Belotte J, Saed MG, Memaj I, Diamond MP, Morris RT, Saed GM. Specific point mutations in key redox enzymes are associated with chemoresistance in epithelial ovarian cancer. Free Radic Biol Med. 2017;102:122–32. https://doi.org/10.1016/j.freeradbiomed.2016.11.028.

    Article  CAS  Google Scholar 

  31. Howe GA, Addison CL. β1 integrin: an emerging player in the modulation of tumorigenesis and response to therapy. Cell Adh Migr. 2012;6:71–7. https://doi.org/10.4161/cam.20077.

    Article  Google Scholar 

  32. Işeri ÖD, Kars MD, Arpaci F, Gündüz U. Gene expression analysis of drug-resistant MCF-7 cells: implications for relation to extracellular matrix proteins. Cancer Chemother and Pharmacol. 2010;65:447–55. https://doi.org/10.1007/s00280-009-1048-z.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the Department of Obstetrics and Gynecology at Wayne State University for facilitating this work.

Author information

Authors and Affiliations

  1. Division of Gynecologic Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R, Detroit, MI, 48201, USA

    Amy K. Harper, Robert T. Morris & Ghassan M. Saed

  2. Department of Obstetrics and Gynecology, The C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, 275 E Hancock St, Detroit, MI, 48201, USA

    Thea K. Kirsch-Mangu, Hala Lutfi, Robert T. Morris & Ghassan M. Saed

Authors
  1. Amy K. Harper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thea K. Kirsch-Mangu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hala Lutfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robert T. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ghassan M. Saed
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and supervision: Ghassan M. Saed; methodology: Ghassan Saed, Thea K. Kirsch-Mangu, Hala Lutfi, Amy K. Harper; data collection and analysis: Amy Harper; writing and editing: Ghassan Saed, Thea K Kirsch-Mangu, Robert Morris, Amy K Harper; all authors read and approved the final manuscript.

Corresponding author

Correspondence to Ghassan M. Saed.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Harper, A.K., Kirsch-Mangu, T.K., Lutfi, H. et al. Binding of Intracellular Myeloperoxidase to αV/β1 Integrin Serves as a Mechanism of Survival in Epithelial Ovarian Cancer. Reprod. Sci. 30, 291–300 (2023). https://doi.org/10.1007/s43032-022-01025-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-022-01025-7

Keywords

Search

Navigation