Abstract
Malignant mesothelioma is an aggressive neoplastic proliferation derived from cells lining serosal membranes. The biological and clinical characteristics of epithelial type malignant mesothelioma are distinct from those of biphasic and sarcomatous type tumors. The goal of our study was to examine the molecular basis for this distinction. Microarray analysis confirmed that the molecular signatures of epithelial and biphasic histologic subtypes were distinct. Among the differentially expressed functional gene categories was the ubiquitin–proteasome pathway, which was upregulated in biphasic tumors. Cytotoxicity experiments indicated that 211H cells derived from biphasic tumors were synergistically sensitive to sequential combination regimens containing the proteasome inhibitor bortezomib and oxaliplatin. The mechanism of this synergistic response, which was not detected in cells of epithelial tumor origin, was apoptosis. Together, our results identify the ubiquitin–proteasome pathway as a biomarker of poor prognosis biphasic peritoneal mesothelioma tumors and suggest that proteasome inhibitors could increase the effectiveness of cytotoxic chemotherapy in this subset of patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
Accessions
GenBank/EMBL/DDBJ
References
Adams J . (2003). Cancer Treat Rev 29 (Suppl 1): 3–9.
Adams J . (2004). Nat Rev Cancer 4: 349–360.
Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD et al. (1999). Cancer Res 59: 2615–2622.
Borczuk AC, Gorenstein L, Walter KL, Assaad AA, Wang L, Powell CA . (2003). Am J Pathol 163: 1949–1960.
Borczuk AC, Kim HK, Yegen HA, Friedman RA, Powell CA . (2005a). Am J Respir Crit Care Med 172: 729–737.
Borczuk AC, Taub RN, Hesdorffer M, Hibshoosh H, Chabot JA, Keohan ML et al. (2005b). Clin Cancer Res 11: 3303–3308.
Fahy BN, Schlieman MG, Virudachalam S, Bold RJ . (2003). J Surg Res 113: 88–95.
Fizazi K, Doubre H, Le Chevalier T, Riviere A, Viala J, Daniel C et al. (2003). J Clin Oncol 21: 349–354.
Gentiloni N, Febbraro S, Barone C, Lemmo G, Neri G, Zannoni G et al. (1997). J Clin Gastroenterol 24: 276–279.
Goldblum J, Hart WR . (1995). Am J Surg Pathol 19: 1124–1137.
Gordon GJ, Jensen RV, Hsiao L-L, Gullans SR, Blumenstock JE, Richards WG et al. (2003). J Natl Cancer Inst 95: 598–605.
Gordon GJ, Rockwell GN, Jensen RV, Rheinwald JG, Glickman JN, Aronson JP et al. (2005). Am J Pathol 166: 1827–1840.
Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP . (2003). Nucleic Acids Res 31: e15.
Khalil N, Parekh TV, O'Connor R, Antman N, Kepron W, Yehaulaeshet T et al. (2001). Thorax 56: 907–915.
Kim H, Xu G-L, Borczuk AC, Busch S, Filmus J, Capurro M et al. (2003). Am J Respir Cell Mol Biol 29: 694–701.
Kitagawa Y, Wong F, Lo P, Elliott M, Verburgt LM, Hogg JC et al. (1996). Am J Respir Cell Mol Biol 15: 45–54.
Lee JJ, Trizna Z, Hsu TC, Spitz MR, Hong WK . (1996). Cancer Epidemiol Biomarkers Prev 5: 191–197.
Leu KM, Ostruszka LJ, Shewach D, Zalupski M, Sondak V, Biermann JS et al. (2004). J Clin Oncol 22: 1706–1712.
Lopez-Rios F, Chuai S, Flores R, Shimizu S, Ohno T, Wakahara K et al. (2006). Cancer Res 66: 2970–2979.
McShane LM, Radmacher MD, Freidlin B, Yu R, Li MC, Simon R . (2002). Bioinformatics 18: 1462–1469.
Mohamed F, Sugarbaker PH . (2002). Curr Treat Options Oncol 3: 375–386.
Nawrocki ST, Sweeney-Gotsch B, Takamori R, McConkey DJ . (2004). Mol Cancer Ther 3: 59–70.
Nowak AK, Byrne MJ, Williamson R, Ryan G, Segal A, Fielding D et al. (2002). Br J Cancer 87: 491–496.
Pass HI, Liu Z, Wali A, Bueno R, Land S, Lott D et al. (2004). Clin Cancer Res 10: 849–859.
Rajkumar SV, Richardson PG, Hideshima T, Anderson KC . (2005). J Clin Oncol 23: 630–639.
Reile H, Birnbock H, Bernhardt G, Spruss T, Schonenberger H . (1990). Anal Biochem 187: 262–267.
Ricotti L, Tesei A, De Paola F, Ulivi P, Frassineti GL, Milandri C et al. (2003). Clin Cancer Res 9: 900–905.
Robinson BW, Ostruszka L, Im MM, Shewach DS . (2004). Semin Oncol 31: 2–12.
Schenkein DP . (2005). Clin Lung Cancer 7 (Suppl 2): S49–S55.
Schutte W, Blankenburg T, Lauerwald K, Schreiber J, Bork I, Wollscgkaeger B et al. (2003). Clin Lung Cancer 4: 294–297.
Sebbag G, Yan H, Shmookler BM, Chang D, Sugarbaker PH . (2000). Br J Surg 87: 1587–1593.
Singhal S, Wiewrodt R, Malden LD, Amin KM, Matzie K, Friedberg J et al. (2003). Clin Cancer Res 9: 3080–3097.
Sugarbaker PH, Welch LS, Mohamed F, Glehen O . (2003). Surg Oncol Clin N Am 12: 605–621, xi.
Tallarida RJ . (2001). J Pharmacol Exp Ther 298: 865–872.
Taub RN, Keohan ML, Chabot JC, Fountain KS, Plitsas M . (2000). Curr Treat Options Oncol 1: 303–312.
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P et al. (2003). J Clin Oncol 21: 2636–2644.
Voorhees PM, Dees EC, O'Neil B, Orlowski RZ . (2003). Clin Cancer Res 9: 6316–6325.
Acknowledgements
This work was supported in part by the Columbia University Mesothelioma Center. Bortezomib was provided by Millennium.
Author information
Authors and Affiliations
Corresponding author
Additional information
Grant support: American Cancer Society CRTG00058.
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Rights and permissions
About this article
Cite this article
Borczuk, A., Cappellini, G., Kim, H. et al. Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin–proteasome pathway as a therapeutic target in poor prognosis tumors. Oncogene 26, 610–617 (2007). https://doi.org/10.1038/sj.onc.1209809
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1209809
Keywords
This article is cited by
-
The role of apoptosis defects in malignant mesothelioma pathogenesis with an impact on prognosis and treatment
Cancer Chemotherapy and Pharmacology (2019)
-
Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib-induced apoptosis
Scientific Reports (2017)
-
The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma
Modern Pathology (2016)
-
Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines
Cancer Chemotherapy and Pharmacology (2010)
-
Pathways affected by asbestos exposure in normal and tumour tissue of lung cancer patients
BMC Medical Genomics (2008)