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.

  • Original Article
  • Published:

PSP94 contributes to chemoresistance and its peptide derivative PCK3145 represses tumor growth in ovarian cancer

Oncogene volume 33, pages 5288–5294 (2014)Cite this article

Subjects

Abstract

Tumor drug resistance remains a major challenge in the treatment of cancer. Here, we show that Prostatic secretory protein 94 (PSP94) levels are reduced in ovarian cancer patients with high levels of excision repair cross-complementing 1 (ERCC1), a marker for chemoresistance. We find that PSP94 is decreased in an ovarian cancer drug-resistant cell line, and plays an important role in the development of drug resistance in vitro. Our studies indicate that PSP94 can partially reverse drug resistance in mouse tumor models in vivo and that a PSP94 peptide derivative PCK3145 suppresses chemoresistant cancer cell and tumor growth in vitro and in vivo. Our investigation of the involved molecular mechanisms suggests that PSP94 may confer drug resistance by modulating the Lin28b/Let-7 signaling pathway. We introduce PSP94 and its peptide derivative PCK3145 as potential target to reverse chemoresistance in ovarian cancer and have begun to identify their relevant molecular targets in specific signaling pathways.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Longley DB, Johnston PG . Molecular mechanisms of drug resistance. J Pathol 2005; 205: 275–292.

    Article  CAS  PubMed  Google Scholar 

  2. Redmond KM, Wilson TR, Johnston PG, Longley DB . Resistance mechanisms to cancer chemotherapy. Front Biosci 2008; 13: 5138–5154.

    Article  CAS  PubMed  Google Scholar 

  3. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141: 69–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. Honma K, Iwao-Koizumi K, Takeshita F, Yamamoto Y, Yoshida T, Nishio K et al. RPN2 gene confers docetaxel resistance in breast cancer. Nat Med 2008; 14: 939–948.

    Article  CAS  PubMed  Google Scholar 

  6. Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D et al. beta-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 2010; 18: 606–618.

    Article  CAS  PubMed  Google Scholar 

  7. Chen T . Overcoming drug resistance by regulating nuclear receptors. Adv Drug Deliv Rev 2010; 62: 1257–1264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lage H . An overview of cancer multidrug resistance: a still unsolved problem. Cell Mol Life Sci 2008; 65: 3145–3167.

    Article  CAS  PubMed  Google Scholar 

  9. Lilja H, Abrahamsson PA . Three predominant proteins secreted by the human prostate gland. Prostate 1988; 12: 29–38.

    Article  CAS  PubMed  Google Scholar 

  10. Weiber H, Andersson C, Murne A, Rannevik G, Lindstrom C, Lilja H et al. Beta microseminoprotein is not a prostate-specific protein. Its identification in mucous glands and secretions. Am J Pathol 1990; 137: 593–603.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Baijal-Gupta M, Clarke MW, Finkelman MA, McLachlin CM, Han VK . Prostatic secretory protein (PSP94) expression in human female reproductive tissues, breast and in endometrial cancer cell lines. J Endocrinol 2000; 165: 425–433.

    Article  CAS  PubMed  Google Scholar 

  12. Whitaker HC, Warren AY, Eeles R, Kote-Jarai Z, Neal DE . The potential value of microseminoprotein-beta as a prostate cancer biomarker and therapeutic target. Prostate 2010; 70: 333–340.

    CAS  PubMed  Google Scholar 

  13. Yi Guo BY, Mueller Michael D, Jie Yu Jing . The PSP94→prostasin pathway and early detection of ovarian cancer. AACR (Am Assoc Cancer Res) Annu Meet 2012; 53: abstract 3644.

    Google Scholar 

  14. Bussing I, Slack FJ, Grosshans H . let-7 microRNAs in development, stem cells and cancer. Trends Mol Med 2008; 14: 400–409.

    Article  PubMed  Google Scholar 

  15. Schickel R, Boyerinas B, Park SM, Peter ME . MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene 2008; 27: 5959–5974.

    Article  CAS  PubMed  Google Scholar 

  16. Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B et al. Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA. Nature 2000; 408: 86–89.

    Article  CAS  PubMed  Google Scholar 

  17. Boyerinas B, Park SM, Hau A, Murmann AE, Peter ME . The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer 2010; 17: F19–F36.

    Article  CAS  PubMed  Google Scholar 

  18. Piskounova E, Polytarchou C, Thornton JE, LaPierre RJ, Pothoulakis C, Hagan JP et al. Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 2011; 147: 1066–1079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Viswanathan SR, Daley GQ, Gregory RI . Selective blockade of microRNA processing by Lin28. Science 2008; 320: 97–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Guo Y, Chen Y, Ito H, Watanabe A, Ge X, Kodama T et al. Identification and characterization of lin-28 homolog B (LIN28B) in human hepatocellular carcinoma. Gene 2006; 384: 51–61.

    Article  CAS  PubMed  Google Scholar 

  21. Viswanathan SR, Powers JT, Einhorn W, Hoshida Y, Ng TL, Toffanin S et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet 2009; 41: 843–848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. King CE, Wang L, Winograd R, Madison BB, Mongroo PS, Johnstone CN et al. LIN28B fosters colon cancer migration, invasion and transformation through let-7-dependent and -independent mechanisms. Oncogene 2011; 30: 4185–4193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hagan JP, Piskounova E, Gregory RI . Lin28 recruits the TUTase Zcchc11 to inhibit let-7 maturation in mouse embryonic stem cells. Nat Struct Mol Biol 2009; 16: 1021–1025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ji J, Wang XW . A Yin-Yang balancing act of the lin28/let-7 link in tumorigenesis. J Hepatol 2010; 53: 974–975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dabholkar M, Vionnet J, Bostick-Bruton F, Yu JJ, Reed E, Messenger RNA . levels of XPAC and ERCC1 in ovarian cancer tissue correlate with response to platinum-based chemotherapy. J Clin Invest 1994; 94: 703–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li Q, Yu JJ, Mu C, Yunmbam MK, Slavsky D, Cross CL et al. Association between the level of ERCC-1 expression and the repair of cisplatin-induced DNA damage in human ovarian cancer cells. Anticancer Res 2000; 20: 645–652.

    CAS  PubMed  Google Scholar 

  27. Olaussen KA, Mountzios G, Soria JC . ERCC1 as a risk stratifier in platinum-based chemotherapy for nonsmall-cell lung cancer. Curr Opin Pulm Med 2007; 13: 284–289.

    Article  CAS  PubMed  Google Scholar 

  28. Rabik CA, Dolan ME . Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 2007; 33: 9–23.

    Article  CAS  PubMed  Google Scholar 

  29. Reed E, Yu JJ, Davies A, Gannon J, Armentrout SL . Clear cell tumors have higher mRNA levels of ERCC1 and XPB than other histological types of epithelial ovarian cancer. Clin Cancer Res 2003; 9: 5299–5305.

    CAS  PubMed  Google Scholar 

  30. Shukeir N, Arakelian A, Kadhim S, Garde S, Rabbani SA . Prostate secretory protein PSP-94 decreases tumor growth and hypercalcemia of malignancy in a syngenic in vivo model of prostate cancer. Cancer Res 2003; 63: 2072–2078.

    CAS  PubMed  Google Scholar 

  31. Shukeir N, Arakelian A, Chen G, Garde S, Ruiz M, Panchal C et al. A synthetic 15-mer peptide (PCK3145) derived from prostate secretory protein can reduce tumor growth, experimental skeletal metastases, and malignancy-associated hypercalcemia. Cancer Res 2004; 64: 5370–5377.

    Article  CAS  PubMed  Google Scholar 

  32. Fuchtner C, Emma DA, Manetta A, Gamboa G, Bernstein R, Liao SY . Characterization of a human ovarian carcinoma cell line: UCI 101. Gynecol Oncol 1993; 48: 203–209.

    Article  CAS  PubMed  Google Scholar 

  33. Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A et al. EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 2012; 18: 74–82.

    Article  CAS  Google Scholar 

  34. Bitarte N, Bandres E, Boni V, Zarate R, Rodriguez J, Gonzalez-Huarriz M et al. MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells 2011; 29: 1661–1671.

    Article  CAS  PubMed  Google Scholar 

  35. Chang TC, Zeitels LR, Hwang HW, Chivukula RR, Wentzel EA, Dews M et al. Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation. Proc Natl Acad Sci USA 2009; 106: 3384–3389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chan PS, Chan LW, Xuan JW, Chin JL, Choi HL, Chan FL . In situ hybridization study of PSP94 (prostatic secretory protein of 94 amino acids) expression in human prostates. Prostate 1999; 41: 99–109.

    Article  CAS  PubMed  Google Scholar 

  37. Abrahamsson PA, Lilja H . Three predominant prostatic proteins. Andrologia 1990; 22: 122–131.

    Article  CAS  PubMed  Google Scholar 

  38. Xuan JW, Chin JL, Guo Y, Chambers AF, Finkelman MA, Clarke MW . Alternative splicing of PSP94 (prostatic secretory protein of 94 amino acids) mRNA in prostate tissue. Oncogene 1995; 11: 1041–1047.

    CAS  PubMed  Google Scholar 

  39. Hawkins RE, Daigneault L, Cowan R, Griffiths R, Panchal C, Armstrong A et al. Safety and tolerability of PCK3145, a synthetic peptide derived from prostate secretory protein 94 (PSP94) in metastatic hormone-refractory prostate cancer. Clin Prostate Cancer 2005; 4: 91–99.

    Article  CAS  PubMed  Google Scholar 

  40. Jeong SH, Wu HG, Park WY . LIN28B confers radio-resistance through the posttranscriptional control of KRAS. Exp Mol Med 2009; 41: 912–918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pardoll DM . The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lv K, Liu L, Wang L, Yu J, Liu X, Cheng Y et al. Lin28 Mediates Paclitaxel Resistance by Modulating p21, Rb and Let-7a miRNA in Breast Cancer Cells. PLoS One 2012; 7: e40008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yu J, Dabholkar M, Bennett W, Welsh J, Mu C, Bostickbruton F et al. Platinum-sensitive and platinum-resistant ovarian cancer tissues show differences in the relationships between mRNA levels of p53, ERCC1 and XPA. Int J Oncol 1996; 8: 313–317.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge the Molecular Medicine Core Facility, Mary Babb Randolph Cancer Center, West Virginia University and Icesnow Yanyan Bioscience Association, Beijing for supporting this study.

Author contributions

B-xY, J-xM and JJY conceived and designed the experiments. B-xY, JZ and YG performed the experiments. J-xM analyzed and interpreted the data. B-xY, J-xM, HR and JJY wrote the manuscript. JJY, HR, MDM and SCR finalized the paper.

Author information

Author notes

  1. B-x Yan and J-x Ma: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Department of Basic Pharmaceutical Sciences, School of Medicine, School of Pharmacy and Mary Babb Randolph Cancer Center, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia, USA

    B-x Yan, J-x Ma, Y Guo, H Riedel, M D Mueller, S C Remick & J J Yu

  2. IcesnowYanyan Bioscience Association, Beijing, China

    B-x Yan & J Zhang

  3. Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA

    J-x Ma

  4. Beijing Animal Science Institute, Beijing, China

    J Zhang

Authors
  1. B-x Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J-x Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Riedel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M D Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S C Remick
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J J Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B-x Yan.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yan, Bx., Ma, Jx., Zhang, J. et al. PSP94 contributes to chemoresistance and its peptide derivative PCK3145 represses tumor growth in ovarian cancer. Oncogene 33, 5288–5294 (2014). https://doi.org/10.1038/onc.2013.466

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.466

Keywords

This article is cited by

Search

Advanced search

Quick links