Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicinresistant human cancer cell lines

Zhenfeng Duan, Yifei Duan, Diana E. Lamendola, Rushdia Z. Yusuf, Rizwan C. Naeem, Richard T. Penson, Michael V. Seiden

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

Previous studies directed at identifying paclitaxel resistance genes in a paclitaxel-resistant subclone of the human ovarian cancer cell line SKOV-3 identified a novel cancer testis antigen, Taxol resistance- associated gene 3 (TRAG-3). Because investigation suggested that TRAG-3, located on chromosome Xq28, does not directly participate in the paclitaxel-resistant phenotype, it was hypothesized that TRAG-3 might be linked to a neighboring gene that is directly involved in the drug-resistant phenotype, or alternatively, overexpression of TRAG-3 might be attributable to coregulation with other cancer testis antigens. To distinguish between these two hypotheses, expression of the genes that flank TRAG-3 was evaluated, namely the Centrin 2 gene and several members of the MAGE gene cluster. Northern analysis demonstrates overexpression of MAGE2 but not Centrin 2. Extension of this analysis to other neighboring and non-neighboring representative cancer testis antigens reveals overexpression of MAGE3, MAGE6, MAGE11, and MAGE12, as well as GAGE-2, GAGE-4, GAGE-5, GAGE-6, and GAGE-7 (clustered on Xp11) in SKOV-3TR, as compared with SKOV-3. In addition, Affymetrix-based analysis of gene expression in SKOV-3 subclones with variable paclitaxel resistance demonstrates MAGE gene overexpression occurs early in the development of the paclitaxel-resistant phenotype, whereas GAGE gene overexpression occurs somewhat later. Evaluation of additional breast and ovarian cancer cell lines reveals MAGE/GAGE overexpression in both paclitaxel- and doxorubicin-resistant cell lines, whereas gemcitabine-resistant subclones of several ovarian cancer cell lines, including SKOV-3GR, reveals no change in MAGE/ GAGE expression. To determine whether MAGE gene overexpression contributes directly to the drug-resistant phenotype, MAGE2 or MAGE6, cDNA was introduced into the paclitaxel-sensitive human ovarian cancer cell line OVCAR8. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity analysis of both MAGE2 and MAGE6 transfectants demonstrates a 4-fold increase in resistance to paclitaxel and 2-fold increase in resistance to doxorubicin but not to other drugs, such as topotecan and cisplatin, through a nonmultidrug resistance-1 mechanism. MAGE2 or MAGE6 overexpression also induces a growth advantage in OVCAR8-transfected cells. These studies suggest that the in vitro acquisition of paclitaxel and doxorubicin resistance can be associated with increased expression of a variety of both neighboring and non-neighboring cancer testis antigens genes. This does not appear to be a consequence of random genetic instability or genomic amplification of the X chromosome. These antigens, because of limited expression in normal tissues, may be suitable targets for immunotherapy and novel therapeutic strategies in the treatment of chemotherapy-resistant epithelial tumors.

Original languageEnglish (US)
Pages (from-to)2778-2785
Number of pages8
JournalClinical Cancer Research
Volume9
Issue number7
StatePublished - Jul 1 2003
Externally publishedYes

Fingerprint

Paclitaxel
Cell Line
Genes
Neoplasms
Testicular Neoplasms
Ovarian Neoplasms
Antigens
Doxorubicin
Phenotype
Sulfamethoxazole Drug Combination Trimethoprim
gemcitabine
Pharmaceutical Preparations
Topotecan
Gene Expression
Genomic Instability
X Chromosome
Multigene Family
Immunotherapy
Cisplatin
Complementary DNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Duan, Z., Duan, Y., Lamendola, D. E., Yusuf, R. Z., Naeem, R. C., Penson, R. T., & Seiden, M. V. (2003). Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicinresistant human cancer cell lines. Clinical Cancer Research, 9(7), 2778-2785.

Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicinresistant human cancer cell lines. / Duan, Zhenfeng; Duan, Yifei; Lamendola, Diana E.; Yusuf, Rushdia Z.; Naeem, Rizwan C.; Penson, Richard T.; Seiden, Michael V.

In: Clinical Cancer Research, Vol. 9, No. 7, 01.07.2003, p. 2778-2785.

Research output: Contribution to journalArticle

Duan, Z, Duan, Y, Lamendola, DE, Yusuf, RZ, Naeem, RC, Penson, RT & Seiden, MV 2003, 'Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicinresistant human cancer cell lines', Clinical Cancer Research, vol. 9, no. 7, pp. 2778-2785.
Duan Z, Duan Y, Lamendola DE, Yusuf RZ, Naeem RC, Penson RT et al. Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicinresistant human cancer cell lines. Clinical Cancer Research. 2003 Jul 1;9(7):2778-2785.
Duan, Zhenfeng ; Duan, Yifei ; Lamendola, Diana E. ; Yusuf, Rushdia Z. ; Naeem, Rizwan C. ; Penson, Richard T. ; Seiden, Michael V. / Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicinresistant human cancer cell lines. In: Clinical Cancer Research. 2003 ; Vol. 9, No. 7. pp. 2778-2785.
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