Mitoxantrone Resistance protein (MXR) is down-regulated in colorectal cancer

Abstract

Introduction. MXR knockout mice were recently shown to display a lethal photosensitive phenotype suggesting an inverse relationship between MXR and photosensitivity. Normal human colon expresses MXR, but colorectal cancer is susceptible to photodynamic therapy. We hypothesized that MXR is down regulated in colorectal cancer. Methods. Total RNA was extracted from paired normal and cancer tissues harvested from 13 patients with colorectal cancer. MXR mRNA expression was determined by RT-PCR using 18S RNA as an internal control and confirmed by Northern blot using β-actin mRNA as an internal control. MXR protein expression was determined by immunohistochemistry (IHC). The log of the ratio of relative expression by RT-PCR was analyzed using a linear mixed model that included subject and gel dates as random effects. Means and standard deviations were calculated, and t-tests were used as appropriate. Results. MXR mRNA was present in normal colon and showed a mean decrease of 6.6-fold in cancer by RT-PCR ( P < 0.0001) and a mean decrease of 4.8-fold by Northern blot ( P = 0.0036). The 95% lower confidence interval for relative expression was a 4.6-fold decrease. MXR protein expression was abundant in the brush border of normal colon on IHC and showed a marked decrease in colorectal cancer. Conclusions. MXR is significantly down regulated in human colorectal cancer. MXR effluxes the phototoxin, protoporphyrin IX. MXR knockout mice accumulate protoporphyrin IX and are photosensitive. Selective accumulation of protoporphyrin IX in cancer tissue after systemic administration of a photosensitizing agent is the biochemical basis of photodynamic therapy. This data showing down regulation of MXR in colorectal cancer may provide the molecular basis for colorectal cancer’s susceptibility to photodynamic therapy.