**1. Introduction**

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease, which was described in 1881 by a French dermatologist. In 2000, it was first recognized that mutation in *ABCC6* is responsible for PXE [1]. It is affecting approximately 1:50,000 people worldwide, with the prominent characteristic feature of ectopic mineralization of soft tissues like skin, eyes, and arteries (Figure 1), for which no effective curative treatment is available [2,3]. Moreover, PXE shows similar phenotypic characteristics with other common health problems like kidney diseases (chronic kidney disease (CKD) and nephrocalcinosis) and cardiovascular diseases (coronary heart disease, cardiomyopathy, and dyslipidemia), which makes PXE a complex disorder [4,5].

Different hypotheses were proposed for the factors pathologically involved with PXE. The "Metabolic Hypothesis" stated that decrease or loss of ABCC6 functionality especially in the liver may lead to a decrease in some circulating factors in the blood stream, which should be responsible for preventing ectopic mineralization of soft tissues. The "PXE Cell Hypothesis" stated that absence of ABCC6 in PXE tissues leads to an alteration in cell proliferation due to changes in the biosynthetic pathway and alters cells to extracellular matrix interactions. The most recent "ATP Release Hypothesis" stated that ABCC6 mediates the efflux of ATP in extracellular milieu, where it is hydrolyzed into AMP and pyrophosphate and prevents the mineralization of soft tissues [1].

**Citation:** Bisaccia, F.; Koshal, P.; Abruzzese, V.; Castiglione Morelli, M.A.; Ostuni, A. Structural and Functional Characterization of the ABCC6 Transporter in Hepatic Cells: Role on PXE, Cancer Therapy and Drug Resistance. *Int. J. Mol. Sci.* **2021**, *22*, 2858. https://doi.org/10.3390/ ijms22062858

Academic Editor: Thomas Falguières

Received: 20 February 2021 Accepted: 9 March 2021 Published: 11 March 2021

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Previous studies of serum analysis either from the *ABCC6* knock-down mouse model or from PXE patients showed an inability to prevent calcium and phosphate deposition and suggested that PXE is a metabolic disease with very slow onset [1,6,7]. It should be noted that the tissues, which mostly express ABCC6, are the liver and, to some lesser extent, the kidney and differ from those in which ectopic mineralization is mostly evident, namely soft tissues of skin, eyes, and the cardiovascular system. The origin of this apparent paradox has not been explained yet (Figure 1) [8].

On the basis of our previous studies of the ABCC6 transporter in hepatic cells, the present review is focused on lightening changes in cellular function associated with ABCC6 transporter activity.

**Figure 1.** Pictorial presentation of ABCC6 expression and affected tissues in Pseudoxanthoma **Figure 1.** Pictorial presentation of ABCC6 expression and affected tissues in Pseudoxanthoma elasticum (PXE). The protein is expressed mainly in liver and kidney cells but the main areas involved in ectopic calcification are the elastic tissues of heart, blood vessels, skin, and eyes.
