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 i ncrease resistance to drugs inhibiting DNA replication in RT1080 fibrosarco ma cells. In the present study, two GSE-transduced cell Lines, isolated wit h and without cytotoxic selection, were found to be resistant to a diverse group of DNA-interactive agents, including aphidicolin, hydroxyurea, cytara bine, etoposide, doxorubicin, and mafosfamide. Changes in gene expression a ssociated with GSE-induced drug resistance were analyzed by cDNA array hybr idization and reverse transcription-PCR. Twenty genes were found to be up-r egulated in both of the resistant cell lines. These include genes involved in DNA replication and repair (e.g., PCNA, XRCC1, B-MYB, and GADD45), trans criptional regulators associated with stress response, and cell cycle check point control (e.g., YB-1, DBPA, and ATF4), and genes for signal transducti on proteins (e.g., protein tyrosine phosphatase 1B and regulatory subunits alpha and beta of cAMP-dependent protein kinase). The observed changes in g ene expression may play a role in pleiotropic resistance to different class es of DNA-targeting drugs.