Pleiotropic Resistance to DNA-interactive Drugs Is Associated with Increased Expression of Genes Involved in DNA Replication, Repair, and Stress Response

A combination of four genetic suppressor elements (GSEs), two of which are derived from putative transcriptional regulators, was previously found to increase resistance to drugs inhibiting DNA replication in HT1080 fibrosarcoma cells. In the present study, two GSE-transduced cell lines, isolated with and without cytotoxic selection, were found to be resistant to a diverse group of DNA-interactive agents, including aphidicolin, hydroxyurea, cytarabine, etoposide, doxorubicin, and mafosfamide. Changes in gene expression associated with GSE-induced drug resistance were analyzed by cDNA array hybridization and reverse transcription-PCR. Twenty genes were found to be up-regulated in both of the resistant cell lines. These include genes involved in DNA replication and repair ( e.g., PCNA , XRCC1 , B-MYB , and GADD45 ), transcriptional regulators associated with stress response, and cell cycle checkpoint control ( e.g., YB-1 , DBPA , and ATF4 ), and genes for signal transduction proteins ( e.g., protein tyrosine phosphatase 1B and regulatory subunits α and β of cAMP-dependent protein kinase). The observed changes in gene expression may play a role in pleiotropic resistance to different classes of DNA-targeting drugs.