Aberrant transcription from an unrelated promoter can result in MDR-1 expression following drug selection in vitro and in relapsed lymphoma samples.
The development of drug resistance in the treatment of cancer remains a major problem. The hallmark of multidrug resistance is cross-resistance to multiple structurally unrelated compounds. The MDR-1 gene encoding P-glycoprotein mediates one of the most extensively studied mechanisms of drug resistance. Previous studies led to the proposal that two promoters control expression of the MDR-1 gene, and these were designated the upstream and downstream promoters. In the present article, we provide evidence that transcripts originating from the putative upstream promoter of MDR-1 are in fact aberrant transcripts whose expression is regulated by nearby genomic sequences that include a human endogenous retroviral long terminal repeat (LTR). Expression of this LTR occurs in all cells. We show that following drug selection, especially in cases where gene amplification has occurred, MDR-1 transcripts can begin near this retroviral LTR with transcription proceeding in the direction opposite of the usual LTR transcription. Because expression of these aberrant MDR-1 transcripts (AMT) is found primarily in drug-resistant cell lines, we conclude that the development of drug resistance or the attendant drug exposure might have a role in the activation of this phenomenon or the selection of cells expressing AMTs. Demonstration of similar aberrant transcripts in tumor samples obtained from patients with relapsed lymphoma suggests that this phenomenon may also occur clinically.
Huff
Lyn Mickley
LM
Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Wang
Zheng
Z
Iglesias
Angel
A
Fojo
Tito
T
Lee
Jong-Seok
JS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics; D008969:Molecular Sequence Data; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020079:Terminal Repeat Sequences; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents