Direct activation of the human major vault protein gene by DNA-damaging agents

Abstract

Vaults are barrel-shaped cytoplasmic ribonucleoprotein particles composed of three proteins. One of the components, the major vault protein (MVP) initially named the lung resistance-related protein (LRP), was found to be overexpressed in various multidrug resistant cancer cell lines and clinical samples. In this study, we investigated whether anticancer drugs could directly induce MVP protein or gene expression in the SW-620 human colorectal cancer cell line, in which MVP has been shown to be induced by the differentiation-inducing agent, sodium butyrate (NaB). MVP protein levels were enhanced in SW-620 cells after a 72 h treatment with doxorubicin (Adr), etoposide (VP-16), cis-platinum (II) diammine dichloride (CDDP) or SN-38, but not vincristine (VCR) or paclitaxel (Taxol) at their IC50 concentration. Treatment for 48 h with Adr, VP-16 and SN-38 at their IC50 concentration also enhanced the expression of MVP mRNA. Moreover, Adr could directly enhance the transcriptional activity of MVP promoter regions. On the other hand, the Adr treatment did not affect the stability of MVP mRNA. Furthermore, MVP levels were also elevated after treatment with the DNA-damaging agents, ethidium bromide (EtBr) and ultraviolet light (UV) irradiation. Our findings therefore suggest that DNA damage enhances MVP promoter activity. Since the MVP protein and mRNA have low turnover rates, a slight enhancement of MVP promoter activity could lead to a considerable increase in the level of MVP.