ABCC11/MRP8 Expression in the Gastrointestinal Tract and a Novel Role for Pepsinogen Secretion

Abstract

ATP-binding cassette (ABC) transporters are involved in chemotherapy resistance. Multidrug-resistance protein 8 (ABCC11/MRP8) is also involved in 5-fluorouracil (5-FU) metabolism. 5-FU and its derivatives are widely used in the treatment of gastrointestinal tract cancers, but little is known about the contribution of ABCC11/MRP8 to gastrointestinal tract and related cancers. Here, we report our investigation of ABCC11/MRP8 expression in normal and cancerous gastrointestinal tract tissues and reveal its novel role in the gastric mucosa. In tissue microarray and surgically resected cancer specimens, immunohistochemical (IHC) staining revealed significantly reduced expression of ABCC11/MRP8 in gastrointestinal tract cancers compared with other cancers. In contrast, strong ABCC11/MRP8 expression was observed in normal gastric mucosa. Additional immuno­fluorescence assays revealed co-localization of ABCC11/MRP8 and pepsinogen I in normal gastric chief cells. Quantitative PCR and Western blot analysis also revealed significant expression of ABCC11/MRP8 in fundic mucosa where the chief cells are mainly located. Furthermore, the ABCC11 mRNA-suppressed NCI-N87 gastric cancer cell line failed to secret pepsinogen I extracellularly. Thus, low expression of ABCC11/MRP8 is consistent with chemotherapeutic regimens using 5-FU and its derivatives in gastrointestinal tract cancers. Our results indicated a novel function of ABCC11/MRP8 in the regulation of pepsinogen I secretion in the normal gastric chief cells.

Induced Expression of Cancer Stem Cell Markers ALDH1A3 and Sox-2 in Hierarchical Reconstitution of Apoptosis-resistant Human Breast Cancer Cells

“…Primary antibody binding was detected using Alexa Fluor 488 conjugated goat anti-rabbit IgG (Life technologies, USA, 1:1000) and Alexa Fluor 680 conjugated goat anti-mouse IgG (Life technologies, USA, 1:1000) secondary antibodies [27]. The cells were mounted and counterstained with DAPI (4,6-diamidino-2-phenylindole, dihydrochloride, 300 μgmL) (Molecular Probes, USA) for nuclear staining [28]. Fluorescence images were captured with a confocal laser scanning microscope (A1, NIKON InSTECH, Tokyo, Japan).…”

The Importance of Steroid Uptake and Intracrine Action in Endometrial and Ovarian Cancers

“…ABCC11 (MRP8) is found in brain, breasts, lungs, liver, kidney, placenta, prostate, testes, and apocrine glands, as well as in cancerous tissues (Kruh et al, 2007 ). Its substrates are lipophilic anions, as well as cyclic nucleotides and anticancer drugs (Bortfeld et al, 2006 ; Matsumoto et al, 2014 ). ABCC1, ABCC11, and ABCG2 transport E1-S, while ABCC1, ABCC4, ABCC11, and ABCG2 mediate excretion of DHEA-S (Table 2 ).…”

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

“…However, the effect of MRP8 genotypes on breast cancer is likely to be more complex since there are studies showing that the association could not be observed in Caucasian (82). Although there is a report showing a decrease in MRP8 level in breast cancer (83), high level of MRP8 was reported in breast cancer and gastric cancer cell lines by other groups (84,85). Other substrates of MRP8 include MTX (79), 5-FU, and pemetrexed (86,87).…”