Skip to main content

Advertisement

SpringerLink
Log in

Evaluation of RIP1K and RIP3K expressions in the malignant and benign breast tumors

  • Original Article
  • Published:
Tumor Biology

Abstract

Receptor-interacting protein kinase 1 (RIP1K) and RIP3K belong to RIPK family, which regulate cell survival and cell death. In the present investigation, the expression levels of RIP1K and RIP3K were evaluated in the 30 malignant, 15 benign, and 20 normal breast tissues, and their correlation with clinicopathological characteristics was also studied. The expression levels of RIP1K and RIP3K were determined, by western blot analysis. The relative RIP1K expression was significantly higher in the malignant and benign tumors when compared to those of normal tissues (P < 0.0001 and P < 0.001, respectively). However, the expression level of RIP3K was significantly lower in the malignant tumors than those of normal and benign values (P < 0.001 and P < 0.01, respectively). Positive significant correlation was found for RIP1K expression with tumor size (P < 0.001), grades (P < 0.0001), and c-erbB2 (P < 0.001), but negative significant correlation was detected with patient’s age (P < 0.001), estrogen receptor (ER) (P < 0.001), progesterone receptor (PR) (P < 0.01), and P53 (P<0.01) status. RIP3K expression was significantly lower in the pre-menopauses (P < 0.01), grade III (P < 0.05), ER-negative (P < 0.05), and c-erbB2-negative malignant tumors, but no correlation was detected with tumor size, PR, and P53 status. No significant correlation was observed for RIP1K and RIP3K expressions with Ki67 and Her2. Based on the present results, it is concluded that reduction of RIP3K expression in the malignant breast tumor might be an important evidence to support the antitumor activity of this enzyme in vivo. However, RIP1K expression was shown to be higher in the malignant breast tumors than those of normal and benign breast tissues, which probably designates as a poor prognostic factor.

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

Similar content being viewed by others

Abbreviations

RIP1K:

Receptor-interacting protein kinase 1

RIP3K:

Receptor-interacting protein kinase 3

ER:

Estrogen receptor

PR:

Progesterone receptor

References

  1. Ofengeim D, Y. J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat Rev Mol Cell Biol. 2013;14:727–36.

    Article  CAS  PubMed  Google Scholar 

  2. Moriwaki K, Chan FK. RIP3: a molecular switch for necrosis and inflammation. Genes Dev. 2013;27:1640–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang D, Lin J, Han J. Receptor-interacting protein (RIP) kinase family. Cell Mol Immunol. 2010;7:243–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137:1112–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sosna J, Voigt S, Mathieu S, Lange A, Thon L, Davarnia P, et al. TNF-induced necroptosis and PARP-1-mediated necrosis represent distinct routes to programmed necrotic cell death. Cell Mol Life Sci. 2014;71:331–48.

    Article  CAS  PubMed  Google Scholar 

  6. Cho Y, McQuade T, Zhang H, Zhang J, Chan FK. RIP1-dependent and independent effects of necrostatin-1 in necrosis and t cell activation. PLoS One. 2011;6, e23209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Green DR, Oberst A, Dillon CP, Weinlich R, Salvesen GS. RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol Cell. 2011;44:9–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Maki JL, Tres Brazell J, Teng X, Cuny GD, Degterev A. Expression and purification of active receptor interacting protein 1 kinase using a baculovirus system. Protein Expr Purif. 2013;89:156–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bertrand MJ, Milutinovic S, Dickson KM, Ho WC, Boudreault A, Durkin J, et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination. Mol Cell. 2008;30:689–700.

    Article  CAS  PubMed  Google Scholar 

  10. Ramnarain DB, Paulmurugan R, Park S, Mickey BE, Asaithamby A, Saha D, et al. RIP1 links inflammatory and growth factor signaling pathways by regulating expression of the EGFR. Cell Death Differ. 2008;15:344–53.

    Article  CAS  PubMed  Google Scholar 

  11. Moriwaki K, Bertin J, Gough PJ, Orlowski GM, Chan FK. Differential roles of RIPK1 and RIPK3 in TNF-induced necroptosis and chemotherapeutic agent-induced cell death. Cell Death Dis. 2015;6, e1636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. O'Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R, Xavier R, et al. Caspase 8 inhibits programmed necrosis by processing cyld. Nat Cell Biol. 2011;13:1437–42.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Feoktistova M, Leverkus M. Programmed necrosis and necroptosis signalling. FEBS J. 2015;282:19–31.

    Article  CAS  PubMed  Google Scholar 

  14. Su X, Wang H, Kang D, Zhu J, Sun Q, Li T, et al. Necrostatin-1 ameliorates intracerebral hemorrhage-induced brain injury in mice through inhibiting RIP1/RIP3 pathway. Neurochem Res. 2015;40:643–50.

    Article  CAS  PubMed  Google Scholar 

  15. Vandenabeele P, Grootjans S, Callewaert N, Takahashi N. Necrostatin-1 blocks both RIPK1 and ido: consequences for the study of cell death in experimental disease models. Cell Death and Differentiation. 2013;20:185–7.

    Article  CAS  PubMed  Google Scholar 

  16. Declercq W, Vanden Berghe T, Vandenabeele P. RIP kinases at the crossroads of cell death and survival. Cell. 2009;138:229–32.

    Article  CAS  PubMed  Google Scholar 

  17. Salami S, Karami-Tehrani F. Biochemical studies of apoptosis induced by tamoxifen in estrogen receptor positive and negative breast cancer cell lines. Clin Biochem. 2003;36:247–53.

    Article  CAS  PubMed  Google Scholar 

  18. Tavakoli-Yaraki M, Karami-Tehrani F, Salimi V, Sirati-Sabet M. Induction of apoptosis by trichostatin a in human breast cancer cell lines: Involvement of 15-LOX-1. Tumour Biol. 2013;34:241–9.

    Article  CAS  PubMed  Google Scholar 

  19. Aghaei M, Karami-Tehrani F, Salami S, Atri M. Adenosine deaminase activity in the serum and malignant tumors of breast cancer: the assessment of isoenzyme ADA1 and ADA2 activities. Clin Biochem. 2005;38:887–91.

    Article  CAS  PubMed  Google Scholar 

  20. Zhou W, Yuan J. Necroptosis in health and diseases. Seminars in cell and developmental biology. 2014;35:14–23.

    Article  PubMed  Google Scholar 

  21. de Almagro MC, Vucic D. Necroptosis: pathway diversity and characteristics. Seminars in cell and developmental biology. 2015;39:56–62.

    Article  PubMed  Google Scholar 

  22. Wang Q, Chen W, Xu X, Li B, He W, Padilla MT, et al. RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species. Carcinogenesis. 2013;34:2119–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang Q, Chen W, Bai L, Chen W, Padilla MT, Lin AS, et al. Receptor-interacting protein 1 increases chemoresistance by maintaining inhibitor of apoptosis protein levels and reducing reactive oxygen species through a microRNA-146a-mediated catalase pathway. J Biol Chem. 2014;289:5654–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yu S, Hou D, Chen P, Zhang Q, Lv B, Ma Y, et al. Adenosine induces apoptosis through TNFR1/RIPK1/p38 axis in colon cancer cells. Biochem Biophys Res Commun. 2015;460:759–65.

    Article  CAS  PubMed  Google Scholar 

  25. Liu XY, Lai F, Yan XG, Jiang CC, Guo ST, Wang CY, et al. RIP1 kinase is an oncogenic driver in melanoma. Cancer Res. 2015;75:1736–48.

    Article  CAS  PubMed  Google Scholar 

  26. Park S, Hatanpaa KJ, Xie Y, Mickey BE, Madden CJ, Raisanen JM, et al. The receptor interacting protein 1 inhibits p53 induction through nf-kappab activation and confers a worse prognosis in glioblastoma. Cancer Res. 2009;69:2809–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. He S, Wang L, Miao L, Wang T, Du F, Zhao L, et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137:1100–11.

    Article  CAS  PubMed  Google Scholar 

  28. Shahsavari Z, Karami-Tehrani F, Salami S, Ghasemzadeh M. RIP1K and RIP3K provoked by shikonin induces cell cycle arrest in the triple negative breast cancer cell line, MDA-MB-468: necroptosis as a desperate programmed suicide pathway. Tumor Biology. 2015.

  29. Koo GB, Morgan MJ, Lee DG, Kim WJ, Yoon JH, Koo JS, et al. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res. 2015;25:707–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Idirisinghe PK, Thike AA, Cheok PY, Tse GM, Lui PC, Fook-Chong S, et al. Hormone receptor and c-erbB2 status in distant metastatic and locally recurrent breast cancer. pathologic correlations and clinical significance. Am J Clin Pathol. 2010;133:416–29.

    Article  PubMed  Google Scholar 

  31. Lee A, Park WC, Yim HW, Lee MA, Park G, Lee KY. Expression of c-erbB2, cyclin D1 and estrogen receptor and their clinical implications in the invasive ductal carcinoma of the breast. Jpn J Clin Oncol. 2007;37:708–14.

    Article  PubMed  Google Scholar 

  32. Inwald EC, Klinkhammer-Schalke M, Hofstädter F, Zeman F, Koller M, Gerstenhauer M, et al. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat. 2013;139:539–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Panjehpour M, Karami-Tehrani F. An adenosine analog (IB-MECA) inhibits anchorage-dependent cell growth of various human breast cancer cell lines. Int J Biochem Cell Biol. 2004;36:1502–9.

    Article  CAS  PubMed  Google Scholar 

  34. Hashemi M, Karami-Tehrani F, Ghavami S, Maddika S, Los M. Adenosine and deoxyadenosine induces apoptosis in oestrogen receptor-positive and -negative human breast cancer cells via the intrinsic pathway. Cell Prolif. 2005;38:269–85.

    Article  CAS  PubMed  Google Scholar 

  35. Panjehpour M, Karami-Tehrani F. Adenosine modulates cell growth in the human breast cancer cells via adenosine receptors. Oncol Res. 2007;16:575–85.

    Article  CAS  PubMed  Google Scholar 

  36. Aghaei M, Panjehpour M, Karami-Tehrani F, Salami S. Molecular mechanisms of A3 adenosine receptor-induced G1 cell cycle arrest and apoptosis in androgen-dependent and independent prostate cancer cell lines: Involvement of intrinsic pathway. J Cancer Res Clin Oncol. 2011;137:1511–23.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Part of this work was supported by a MSc grant from Tarbiat Modares University. We thank the cancer surgery department of Iran’s Day and Bahman Hospitals. We also thank Mrs. Batoul Etemadi-Kia, lab expert, for her kind assistance.

Author information

Authors and Affiliations

  1. Cancer Research Laboratory, Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, P.O. Box 14115-331, Tehran, Iran

    Fatemeh Karami-Tehrani, Amin Rahimi Malek & Zahra Shahsavari

  2. Department of Surgery, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Morteza Atri

Authors
  1. Fatemeh Karami-Tehrani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amin Rahimi Malek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zahra Shahsavari
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morteza Atri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fatemeh Karami-Tehrani.

Ethics declarations

Conflicts of interest

None

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Karami-Tehrani, F., Malek, A.R., Shahsavari, Z. et al. Evaluation of RIP1K and RIP3K expressions in the malignant and benign breast tumors. Tumor Biol. 37, 8849–8856 (2016). https://doi.org/10.1007/s13277-015-4762-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4762-7

Keywords

Search

Navigation