Structural and Functional Characterization of the ABCC6 Transporter in Hepatic Cells: Role on PXE, Cancer Therapy and Drug Resistance

Abstract

Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of a full ABCC6 transporter, which may provide some idea about its physiological role in humans. Some studies suggest that mutations of ABCC6 in the liver lead to a decrease in some circulating factor and indicate that PXE is a metabolic disease. It has been reported that ABCC6 mediates the efflux of ATP, which is hydrolyzed in PPi and AMP; in the extracellular milieu, PPi gives potent anti-mineralization effect, whereas AMP is hydrolyzed to Pi and adenosine which affects some cellular properties by modulating the purinergic pathway. Structural and functional studies have demonstrated that silencing or inhibition of ABCC6 with probenecid changed the expression of several genes and proteins such as NT5E and TNAP, as well as Lamin, and CDK1, which are involved in cell motility and cell cycle. Furthermore, a change in cytoskeleton rearrangement and decreased motility of HepG2 cells makes ABCC6 a potential target for anti-cancer therapy. Collectively, these findings suggested that ABCC6 transporter performs functions that modify both the external and internal compartments of the cells.

Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma

“…[27][28][29] ABCC6 is an ATP-dependent transmembrane transporter, mainly expressed in the liver and kidney, and is a potential target for tumor treatment. [30,31] ABCC7 (CFTR), mainly expressed in colon tissue and skin, regulates ion and liquid transport in epithelial tissues. [32] ABCC8 and ABCC9 are indispensable to the KATP channel, and are closely associated with neonatal diabetes, pulmonary hypertension, and other diseases.…”

“…ABCC5 (MRP5), is an organic anion transporter with excellent ability to transport nucleotides and nucleotide analogs, and is associated with breast cancer bone metastasis and prostate cancer progression [27–29] . ABCC6 is an ATP-dependent transmembrane transporter, mainly expressed in the liver and kidney, and is a potential target for tumor treatment [30,31] . ABCC7 (CFTR), mainly expressed in colon tissue and skin, regulates ion and liquid transport in epithelial tissues [32] .…”

A Novel Idiopathic Atrial Calcification: Pathologic Manifestations and Potential Mechanism

“…Among these identified variants in this patient, several variants have been reported and are associated with PXE. However, it is surprising that this 40 years old patient had no any obvious symptoms of PXE, which is characterized by ectopic calcifications in elastin-rich tissues such as the skin, the Burch's membrane of the retina and the arterial wall ( 67 , 68 ). Being different from PXE, the calcifications of this patient were concentrated on both sides of the atria, presenting a symmetrical distribution of atrial calcifications.…”

The Expression Level of ABCC6 Transporter in Colon Cancer Cells Correlates with the Activation of Different Intracellular Signaling Pathways

“…Studies performed by ours and other groups pointed out that ABCC6 may have different roles due to its activity of ATP efflux transporter [ 46 ]. Besides supplying the extracellular matrix with PPi, a strong inhibitor of mineralization, the transported ATP can contribute to the activation of the extracellular purinergic system, thus affecting cell migration and cytoskeleton rearrangement in cell lines derived from liver cancer, in which ABCC6 is normally expressed.…”