Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance

Kohichiroh Yasui, Saori Mihara, Chen Zhao, Hiroyuki Okamoto, Fumiko Saito-Ohara, Akihiro Tomida, Tadao Funato, Akira Yokomizo, Seiji Naito, Issei Imoto, Takashi Tsuruo, Johji Inazawa

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

Chemoresistance is a major obstacle for successful treatment of cancer. To identify regions of the genome associated with acquired resistance to therapeutic drugs, we conducted molecular cytogenetic analyses of 23 cancer-cell lines, each resistant to either camptothecin, cisplatin, etoposide (VP-16), Adriamycin, or 1-β-D-arabinofuranosylcytosine, although the parental tumor lines were not. Subtractive comparative genomic hybridization studies revealed regions of gain or loss in DNA-copy numbers that were characteristic of drug-resistant cell lines; i.e., differences from their drug-sensitive parental cell lines. Thirteen ATP-binding cassette (ABC) transporter genes [ABCA3, ABCB1 (MDR1), ABCB6, ABCB8, ABCB10, ABCB11, ABCC1 (MRP1), ABCC4, ABCC9, ABCD3, ABCD4, ABCE1, and ABCF2] were amplified among 19 of the resistant cell lines examined. Three genes encoding antiapoptotic BCL-2 proteins (BCL2L2, MCL1, and BCL2L10) were also amplified and consequently overexpressed in three of the derivative lines. Down-regulation of BCL2L2 with an antisense oligonucleotide sensitized a VP-16 resistant ovarian-cancer cell line (SKOV3/ VP) to VP-16. A decrease in copy numbers of genes encoding deoxycytidine kinase, DNA topoisomerase I, and DNA topoisomerase II α reduced their expression levels in one cytosine arabinoside-resistant line, two of three camptothecin-resistant lines, and two of five VP-16-resistant cell lines, respectively. Our results indicated that changes in DNA-copy numbers of the genes mentioned can activate or down-regulate them in drug-resistant cell lines, and that such genomic alterations might be implicated in acquired chemoresistance.

Original languageEnglish
Pages (from-to)1403-1410
Number of pages8
JournalCancer Research
Volume64
Issue number4
DOIs
Publication statusPublished - Feb 15 2004

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yasui, K., Mihara, S., Zhao, C., Okamoto, H., Saito-Ohara, F., Tomida, A., ... Inazawa, J. (2004). Alteration in Copy Numbers of Genes as a Mechanism for Acquired Drug Resistance. Cancer Research, 64(4), 1403-1410. https://doi.org/10.1158/0008-5472.CAN-3263-2