Skip to main content

Advertisement

SpringerLink
Log in

RAIDD expression is impaired in multidrug resistant osteosarcoma cell lines

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To identify the apoptosis genes involved in the multidrug resistant phenotype of osteosarcoma.

Methods

Multidrug resistant human osteosarcoma cell line (U-2 OS MR) and a drug sensitive parental cell line (U-2 OS) were both treated with paclitaxel and analyzed by the gene array containing 96 apoptosis associated genes. The different expression of the special apoptosis associated genes were further analyzed by Western blot in the multidrug resistant osteosarcoma cell lines (U-2 OS MR, KH OS R2) and the drug sensitive parental cell lines (U-2 OS, KH OS). One of the disregulated gene, RAIDD, was transfected into the multidrug resistant osteosarcoma cells for functional studies.

Results

RAIDD showed signs of significant expression in the U-2 OS cells after being treated with paclitaxel (P < 0.01). However, the induction of RAIDD did not occur in U-2 OS MR cells (P = 0.2). Subsequent analysis by Western blot confirmed the deficiency of the expression of RAIDD protein in U-2 OS MR. On the contrary, the expression of RAIDD could be significantly induced by paclitaxel and doxorubicin in U-2 OS cells as both time and dosage were deciding factors. It also demonstrated the cleavage of PARP associated with RAIDD expression in U-2 OS cells, but not however in U-2 OS MR cells after being treated with paclitaxel or doxorubicin. Similar results were found in osteosarcoma multidrug resistant cell line KH OS R2 and the drug sensitive parental cell line KH OS. Furthermore, over-expression of RAIDD in multidrug resistant cell lines could possibly reverse drug resistant phenotypes.

Conclusion

This study indicate that impaired expression of RAIDD in drug induced apoptosis may play a role in the multidrug resistance of osteosarcoma cells.

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
Fig. 7

Similar content being viewed by others

References

  1. Ahmad M, Srinivasula SM, Wang L, Talanian RV, Litwack G, Fernandes-Alnemri T, Alnemri ES (1997) CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP. Cancer Res 57:615–619

    PubMed  CAS  Google Scholar 

  2. Berube C, Boucher LM, Ma W, Wakeham A, Salmena L, Hakem R, Yeh WC, Mak TW, Benchimol S (2005) Apoptosis caused by p53-induced protein with death domain (PIDD) depends on the death adapter protein RAIDD. Proc Natl Acad Sci USA 102:14314–14320

    Article  PubMed  CAS  Google Scholar 

  3. Chou AJ, Gorlick R (2006) Chemotherapy resistance in osteosarcoma: current challenges and future directions. Expert Rev Anticancer Ther 6:1075–1085

    Article  PubMed  CAS  Google Scholar 

  4. Duan H, Dixit VM (1997) RAIDD is a new ‘death’ adaptor molecule. Nature 385:86–89

    Article  PubMed  CAS  Google Scholar 

  5. Duan Z, Duan Y, Lamendola DE, Yusuf RZ, Naeem R, Penson RT, Seiden MV (2003) Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicin-resistant human cancer cell lines. Clin Cancer Res 9:2778–2785

    PubMed  CAS  Google Scholar 

  6. Fayette J, Blay JY (2005) Genetic predictors for drug resistance in soft tissue sarcoma: a review of publications in 2004. Curr Opin Oncol 17:370–375

    Article  PubMed  Google Scholar 

  7. Hannun YA (1997) Apoptosis and the dilemma of cancer chemotherapy. Blood 89:1845–1853

    PubMed  CAS  Google Scholar 

  8. Hunter AM, LaCasse EC, Korneluk RG (2007) The inhibitors of apoptosis (IAPs) as cancer targets. Apoptosis 12:1543–1568

    Article  PubMed  CAS  Google Scholar 

  9. Johnstone RW, Ruefli AA, Lowe SW (2002) Apoptosis: a link between cancer genetics and chemotherapy. Cell 108:153–164

    Article  PubMed  CAS  Google Scholar 

  10. Liu F, Xie ZH, Cai GP, Jiang YY (2007) The effect of survivin on multidrug resistance mediated by P-glycoprotein in MCF-7 and its adriamycin resistant cells. Biol Pharm Bull 30:2279–2283

    Article  PubMed  CAS  Google Scholar 

  11. Lourda M, Trougakos IP, Gonos ES (2007) Development of resistance to chemotherapeutic drugs in human osteosarcoma cell lines largely depends on up-regulation of Clusterin/Apolipoprotein J. Int J Cancer 120:611–622

    Article  PubMed  CAS  Google Scholar 

  12. Lowe SW, Lin AW (2000) Apoptosis in cancer. Carcinogenesis 21:485–495

    Article  PubMed  CAS  Google Scholar 

  13. Makin G, Hickman JA (2000) Apoptosis and cancer chemotherapy. Cell Tissue Res 301:143–152

    Article  PubMed  CAS  Google Scholar 

  14. Marcove RC, Mike V, Hajek JV, Levin AG, Hutter RV (1970) Osteogenic sarcoma under the age of twenty-one. A review of one hundred and forty-five operative cases. J Bone Joint Surg Am 52:411–423

    PubMed  CAS  Google Scholar 

  15. Mimeault M, Hauke R, Batra SK (2007) Recent Advances on the Molecular Mechanisms Involved in the Drug Resistance of Cancer Cells and Novel Targeting Therapies. Clin Pharmacol Ther 83:673–691

    Article  PubMed  Google Scholar 

  16. Park HH, Logette E, Raunser S, Cuenin S, Walz T, Tschopp J, Wu H (2007) Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128:533–546

    Article  PubMed  CAS  Google Scholar 

  17. Park HH, Wu H (2006) Crystal structure of RAIDD death domain implicates potential mechanism of PIDDosome assembly. J Mol Biol 357:358–364

    Article  PubMed  CAS  Google Scholar 

  18. Perego P, Righetti SC, Supino R, Delia D, Caserini C, Carenini N, Bedogne B, Broome E, Krajewski S, Reed JC, Zunino F (1997) Role of apoptosis and apoptosis-related proteins in the cisplatin-resistant phenotype of human tumor cell lines. Apoptosis 2:540–548

    Article  PubMed  CAS  Google Scholar 

  19. Pick R, Badura S, Bosser S, Zornig M (2006) Upon intracellular processing, the C-terminal death domain-containing fragment of the p53-inducible PIDD/LRDD protein translocates to the nucleoli and interacts with nucleolin. Biochem Biophys Res Commun 349:1329–1338

    Article  PubMed  CAS  Google Scholar 

  20. Prabhudesai SG, Rekhraj S, Roberts G, Darzi AW, Ziprin P (2007) Apoptosis and chemo-resistance in colorectal cancer. J Surg Oncol 96:77–88

    Article  PubMed  CAS  Google Scholar 

  21. Provisor AJ, Ettinger LJ, Nachman JB, Krailo MD, Makley JT, Yunis EJ, Huvos AG, Betcher DL, Baum ES, Kisker CT, Miser JS (1997) Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: a report from the Children’s Cancer Group. J Clin Oncol 15:76–84

    PubMed  CAS  Google Scholar 

  22. Schwartz CL, Gorlick R, Teot L, Krailo M, Chen Z, Goorin A, Grier HE, Bernstein ML, Meyers P (2007) Multiple drug resistance in osteogenic sarcoma: INT0133 from the Children’s Oncology Group. J Clin Oncol 25:2057–2062

    Article  PubMed  Google Scholar 

  23. Shearwin-Whyatt LM, Harvey NL, Kumar S (2000) Subcellular localization and CARD-dependent oligomerization of the death adaptor RAIDD. Cell Death Differ 7:155–165

    Article  PubMed  CAS  Google Scholar 

  24. Sturm I, Petrowsky H, Volz R, Lorenz M, Radetzki S, Hillebrand T, Wolff G, Hauptmann S, Dorken B, Daniel PT (2001) Analysis of p53/BAX/p16(ink4a/CDKN2) in esophageal squamous cell carcinoma: high BAX and p16(ink4a/CDKN2) identifies patients with good prognosis. J Clin Oncol 19:2272–2281

    PubMed  CAS  Google Scholar 

  25. Tinel A, Tschopp J (2004) The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304:843–846

    Article  PubMed  CAS  Google Scholar 

  26. Tu S, McStay GP, Boucher LM, Mak T, Beere HM, Green DR (2006) In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis. Nat Cell Biol 8:72–77

    Article  PubMed  CAS  Google Scholar 

  27. Vakifahmetoglu H, Olsson M, Orrenius S, Zhivotovsky B (2006) Functional connection between p53 and caspase-2 is essential for apoptosis induced by DNA damage. Oncogene 25:5683–5692

    Article  PubMed  CAS  Google Scholar 

  28. Violette S, Poulain L, Dussaulx E, Pepin D, Faussat AM, Chambaz J, Lacorte JM, Staedel C, Lesuffleur T (2002) Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status. Int J Cancer 98:498–504

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dr. C. Yang is supported through a grant from the Chinese Council of Scholarship. Dr. Z. Duan is supported, in part, through a grant from the National Cancer Institute, NIH (Nanotechnology Platform Partnership), R01-CA119617. Support has also been provided by the Gaetagno and Wechsler funds.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Massachusetts General Hospital, Boston, MA, 02114, USA

    Cao Yang, Francis J. Hornicek, Kirkham B. Wood, Joseph H. Schwab, Henry Mankin & Zhenfeng Duan

  2. Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, 02114, USA

    Cao Yang, Francis J. Hornicek, Joseph H. Schwab, Henry Mankin & Zhenfeng Duan

  3. Department of Orthopaedic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China

    Cao Yang

Authors
  1. Cao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francis J. Hornicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kirkham B. Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph H. Schwab
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Henry Mankin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhenfeng Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhenfeng Duan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, C., Hornicek, F.J., Wood, K.B. et al. RAIDD expression is impaired in multidrug resistant osteosarcoma cell lines. Cancer Chemother Pharmacol 64, 607–614 (2009). https://doi.org/10.1007/s00280-008-0912-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-008-0912-6

Keywords

Search

Navigation