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ABC transporters bind and hydrolyze ATP to enable active transport of various substrates across cell membranes of diverse cell types. Many of the ABC transporters are involved in the transport of drugs, xenobiotics and endogenous substances and thus play important roles in physiology as well as pharmacology. ABCC3 belongs to the ABCC subfamily, composed of 13 members in mammals, and divided into 3 classes: multi-drug resistance proteins (MRPs), sulfonylurea receptors and cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7). ABCC3 has considerable overlap in substrate specificity with ABCC2. In addition to transporting a broad range of glucuronide conjugates such as bilirubin diglucuronide, ABCC3 is known to transport various bile salts (glycocholate, taurocholate, taurochenodeoxycholate-3-sulfate, taurolithocholate-3-sulfate) and several clinically important anionic drugs such as MTX, etoposide, and its toxic metabolite 7-hydroxymethotrexate. ABCC3 is expressed not only in the liver and intestine but also in the adrenal gland, kidney and pancreas. In the liver and intestine, it localizes to the basolateral membrane of hepatocytes and enterocytes, respectively, where it mediates the efflux of substrates from the cells into the blood.
ABCC3-mediated transport in the hepatocyte
Although ABCC3 is not abundantly present in the healthy liver, a strong upregulation of ABCC3 is observed when the ABCC2 function is decreased or absent. Moreover, ABCC3 is upregulated in cholestatic livers of humans and rats. These observations indicate a toxicological defense function of ABCC3, in which ABCC3 eliminates a range of (toxic) anions from hepatocytes in case of ABCC2 deficiency and/or otherwise impaired biliary secretion. Although ABCC3 does not play an important role in normal bilirubin transport, it provides an alternative bilirubin detoxification pathway through transporting conjugated bilirubin from hepatocytes back into the blood, after which it can be excreted into the urine. In addition, ABCC3 is speculated to play a role in cholehepatic and enterohepatic circulation of bile salts, enabling recycling of bile salts via the liver to promote the generation of bile. ABCC3 expression is also elevated in human hepatocellular carcinomas, primary ovarian cancer and adult acute lymphoid leukemia, where it can confer resistance to teniposide, MTX, and etoposide. Thus, ABCC3 is a potential sanguine biomarker and anticancer target in hepatocellular carcinoma.
Figure 1. ABCC2 and ABCC3-mediated transport in the hepatocyte. (van der Schoor L W E, et al. 2015)
ABCC3 as A Target for the Treatment of Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy. The data indicated that ABCC3 regulates PDAC cell proliferation in vitro and in vivo through the release of lysophosphatidylinositol (LPI), which is a crucial role in PDAC progression and the transporter responsible for its secretion. Besides, studies showed that ABCC3 regulates STAT3 and HIF1α signaling pathways, key regulators of PDAC development and progression. It has been reported that constitutive activation of STAT3 signaling negatively affects the survival of PDAC patients. The ABCC3-regulated function of HIF1α and STAT3 may represent the potential mechanism of ABCC3- mediated PDAC progression. In addition to the high chemoresistance of PDAC tumors, the unsuccessful outcome of most clinical trials in PDAC can also be attributed to the lack of proper stratification of patients into cohorts and to the failure to target therapies based on the mutational landscape. The expression of ABCC3 depends on the genetic status of TP53, one of the main genes dysregulated in PDAC. The correlation of ABCC3 expression with p53 status, as well as LPI-mediated regulation of key signaling pathways in PDAC biology, enhances the importance of ABCC3 in PDAC. ABCC3 could be a promising therapeutic target in pancreatic cancer, which potential should be explored clinically.
ABCC3 Gene Editing Service
CRISPR/Cas9 PlatformCB, a global leading biotechnological company specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control ABCC3 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.
|Service||Details||Alternative cell lines or animal species|
|ABCC3 Gene Editing Cell Line Generation||HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.|
|ABCC3 Gene Editing Animal Model Generation||Mouse, rat, rabbit, zebrafish, C. elegans, etc.|
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