FAU regulates carboplatin resistance in ovarian cancer (original) (raw)

Abstract

The development of chemotherapy resistance by cancer cells is complex, using different mechanisms and pathways. The gene FAU (Finkel-Biskis-Reilly murine sarcoma virus (FBR-MuSV)-associated ubiquitously expressed gene) was identified through functional expression cloning and previous data have shown that overexpression enhances apoptosis in several cell types. We demonstrate that the expression of FAU was reduced in the A2780cis (cisplatin resistant subclone of A2780) cell line compared with the A2780 ovarian cancer cell line, and was directly related to the cell line's sensitivity to carboplatin. Downregulation of FAU in the A2780 cell line by transfection with two predesigned short-interfering RNAs (siRNAs) to FAU resulted in a significant increase in resistance to carboplatin-induced cell death. Downregulation resulted in increased cell viability and reduced apoptosis after 72 hr of drug treatment compared with the negative controls (Kruskal-Wallis P ¼ 0.0002). Transfection of the A2780cis cell line with the pcDNA3 plasmid containing FAU was associated with increased sensitivity to carboplatin-induced apoptosis, with decreased cell viability and increased apoptosis (Mann Whitney P < 0.0001). The expression of FAU was examined by quantitative real-time reverse transcriptase polymerase chain reaction in normal and malignant ovarian tissue. A significant reduction in the expression of FAU was seen in the malignant compared with normal ovarian samples (Kruskal-Wallis P ¼ 0.0261). These data support a role for FAU in the regulation of platinum-resistance in ovarian cancer. Further research is needed into the apoptotic pathway containing FAU to investigate the potential for targeted therapies to increase or restore the platinum sensitivity of ovarian cancer.

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References (34)

  1. Abba MC, Drake JA, Hawkins KA, Hu Y, Sun H, Notcovich C, Gaddis S, Sahin A, Baggerly K, Aldaz CM. 2004. Transcrip- tomic changes in human breast cancer progression as deter- mined by serial analysis of gene expression. Breast Cancer Res 6:R499-R513.
  2. Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, EmmertBuck MR, Debelenko LV, Zhuang ZP, Lubensky IA, Liotta, Crabtree JS, Wang YP, Roe BA, Weisemann J, Boguski MS, Agarwal SK, Kester MB, Kim YS, Heppner C, Dong QH, Spiegel AM, Burns AL, Marx SJ. 1997. Positional cloning of the gene for muliple endocrine neoplasia- type 1. Science 276:404-407.
  3. Dent J, Hall GD, Wilkinson N, Perren TJ, Richmond I, Markham AF, Murphy H, Bell SM. 2003. Cytogenetic alterations in ovar- ian clear cellcarcinoma detected by comparative genomic hybridisation. Br J Cancer 88:1578-1583.
  4. Gray D, Jubb AM, Hogue D, Dowd P, Kljavin N, Yi S, Bai W, Frantz G, Zhang Z, Koeppen H, Sauvage FJ, Davis D. 2005. Maternal embryonic leucine zipper kinas/murine protein serine- threonine kinase 38 is a promising target for multiple cancer. Cancer Res 65:9751-9761.
  5. Guo B, Godzik A, Reed JC. 2001. Bcl-G, a novel pro-apoptotic member of the Bcl-2 family. J Biol Chem 276:2780-2785.
  6. Kas K, Schoenmakers E, van de Ven W, Weber G, Nordenskjold M, Michiels L, Merregeart J, Larsson C. 1993. Assignment of the human FAU gene to a subregion of chromosome 11q13. Genomics 17:387-392.
  7. Kibel AS, Huagen J, Guo C, Isaacs WB, Yan Y, Pienta KJ, Good- fellow PJ. 2004. Expression mapping at 12p 12-13 in advanced prostate carcinoma. Int J Cancer 109:668-672.
  8. Kigawa J, Minagawa Y, Kanamori Y, Itamochi H, Cheng X, Okada M, Oishi T, Terakawa N. 1998. Glutathione concentration may be a useful predictor of response to second-line chemo- therapy in patients with ovarian cancer. Cancer 82:697-702.
  9. Lin ML, Park JH, Nishidate T, Nakamura Y, Katagiri T. 2007. Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with
  10. Bcl-G, a pro-apoptotic member of the Bcl-2 family. Br Cancer Res 9:R17.
  11. Marie SK, Okamoto OK, Uno M, Hasegawa APG, Oba-Shinjo SM, Cohen T, Camargo AA, Kosoy A, Carlotti CG, Toledo S, Moreira-Filho CA, Zago MA, Simpson AJ, Caballero OL. 2008. Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas. Int J Cancer 122:807-815.
  12. Michiels L, Van der Rauwelaert E, Van Hasselt F, Kas K, Merregaert J. 1993. fau cDNA encodes a ubiquitin-like-S30 fusion protein and is expressed as an antisense sequence in Fin- kel-Biskis-Reilly murine sarcoma virus. Oncogene 8:2537-2546.
  13. Milner BJ, Allan LA, Eccles DM, Kitchener HC, Leonard RC, Kelly KF, Parkin DE, Haites NE. 1993. p53 mutation is a common genetic event in ovarian carcinoma. Cancer Res 53:2128-2132.
  14. Mourtada-Maarabouni M, Kirkham L, Farzaneh F, Williams GT. 2004. Regulation of apoptosis by FAU revealed by functional expression cloning and antisense expression. Oncogene 23:9419-9426.
  15. Nakamura M, Tanigawa Y. 2003. Characterization of ubiquitin- like polypeptide acceptor protein, a novel pro-apoptotic member of the Bcl2 family. Eur J Biochem 270:4052-4058.
  16. Nakayama K, Kanzaki A, Terada K, Mutoh M, Oqawa K, Suqiyama T, Takenoshita S, Itoh K, Yaeqashi N, Miyazaki K, Neamati N, Takebayashi Y. 2004. Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy. Clin Cancer Res 10:2804-2811.
  17. Okada S, Tsuda H, Takarabe T, Yoshikawa H, Taketani Y, Hiro- hashi S. 2002. Allelotype analysis of common epithelial ovarian cancers with special reference to comparison between clear cell adenocarcinoma with other histological types. Jpn J Cancer Res 93:798-806.
  18. Penson R, Oliva E, Skates SJ, Glyptis T, Fuller AF, Jr, Goodman A, Seiden MV. 2004. Expression of multidrug resistance-1 pro- tein inversely correlates with paclitaxel response and survival in ovarian cancer patients: A study in serial samples. Gynecol Oncol 93:98-106.
  19. Pickard MR, Green AR, Ellis IO, Caldas C, Hedge VL, Mour- tada-Maarabouni M, Williams GT. 2009. Dysregulation expres- sion of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Res 11:R60.
  20. Richardson A, Kaye SB. 2008. Pharamacological inhibition of the Bcl-2 family of apoptosis regulators as cancer therapy. Curr Mol Pharmacol 1:244-254.
  21. Rossman TG, Wang Z. 1999. Expression cloning for arsenite- resistance resulted in isolation of tumor-suppressor fau cDNA: Possible involvement of the ubiquitin system in arsenic carcino- genesis. Carcinogenesis 20:311-316.
  22. Sankaranarayanan R, Ferlay J. 2006. Worldwide burden of gynae- cological cancer: The size of the problem. Best Pract Res Clin Obstet Gynaecol 20:207-225.
  23. Schrami P, Schwerdtfeger G, Burkhalter F, Raggi A, Schmidt D, Ruffalo T, King W, Wilber K, Mihatsch MJ, Moch H. 2003. Combined array comparative genomic hybridization and tissue microarray suggest PAK1 at 11q13.5-q14 as a critical oncogene target in ovarian carcinoma. Am J Pathol 163:985-992.
  24. Seraj MJ, Samant RS, Verderame MF, Welch DR. 2000. Func- tional evidence for a novel human breast carcinoma metastasis suppressor, MRMS1, encoded at chromosome 11q13. Cancer Res 60:2764-2769.
  25. Shih IeM, Kurman RJ. 2004. A proposed model based on mor- phological and molecular genetic analysis. Am J Pathol 164: 1511-1518.
  26. Singer G, Oldt R, III, Cohen Y, Wang BG, Sidransky D, Kurman RJ, Shih IeM. 2003. Mutations in BRAF and KRAS character- ize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95:484-486.
  27. Strathdee G, MacKean MJ, Illand M, Brown R. 1999. A role for methylation of the hMLH1 promoter in loss of hMLH1 expres- sion and drug resistance in ovarian cancer. Oncogene 18:2335- 2341.
  28. Teneriello MG, Ebina M, Linnoila RI, Henry M, Nash JD, Park RC, Birrer MJ. 1993. P53 and Ki-ras gene mutations in epithe- lial ovarian neoplasms. Cancer Res 53:3103-3108.
  29. Watson RH, Neville PJ, Roy WR, Jr, Hitchcock A, Campbell IG. 1998. Loss of heterozygosity on chromosomes 7p, 7q, 9p and 11q is an early event in ovarian tumorigenesis. Oncogene 17:207-212.
  30. Williams GT, Farzaneh F. 2004. The use of gene function to identify the rate-limiting steps controlling cell fate. Cancer Immunol Immunother 53:160-165.
  31. Williams GT, Hughes JP, Stoneman V, Anderson CL, McCarthy NJ, Mourtada-Maarabouni M, Pickard M, Hedge VL, Trayner I, Farzaneh F. 2006. Isolation of genes controlling apoptosis through their effects on cell survival. Gene Ther Mol Biol 10:255-262.
  32. Wilson TR, Johnston PG, Longley DB. 2009. Anti-apoptotic mechanisms of drug resistance in cancer. Curr Cancer Drug Targets 9:307-319.
  33. Yokoyama Y, Sato S, Fukushi Y, Sakamoto T, Futaqami M, Saito Y. 1999. Significance of multi-drug-resistant proteins in predicting chemotherapy response and prognosis in epithelial ovarian cancer. J Obstet Gynecol 25:387-394.
  34. Genes, Chromosomes & Cancer DOI 10.1002/gcc