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ATP‑Binding Cassette Transporter A1: a Promising Therapy Target for Prostate Cancer (Review)

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ATP‑Binding Cassette Transporter A1: a Promising Therapy Target for Prostate Cancer (Review) MOLECULAR AND CLINICAL ONCOLOGY 8: 9-14, 2018 ATP‑binding cassette transporter A1: A promising therapy target for prostate cancer (Review) TING XIONG1, GANG XU2, XUE-LONG HUANG1, KAI-QIANG LU1, WEI-QUAN XIE1, KAI YIN2 and JIAN TU1 1Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, and 2Department of Diagnostics Teaching and Research, University of South China, Hengyang, Hunan 421001, P.R. China Received May 6, 2017; Accepted November 10, 2017 DOI: 10.3892/mco.2017.1506 Abstract. ATP-binding cassette transporter A1 (ABCA1) Contents has been found to mediate the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I (apoA-I), 1. Introduction and is essential for the synthesis of high-density lipoprotein. 2. Effect of ABCA1 on the progression of prostate cancer Mutations of the ABCA1 gene may induce Tangier disease 3. Association of ABCA1 with apoptosis and autophagy in and familial hypoalphalipoproteinemia; they may also prostate cancer lead to loss of cellular cholesterol homeostasis in prostate 4. ABCA1 and multidrug resistance (MDR) cancer, and increased intracellular cholesterol levels are frequently found in prostate cancer cells. Recent studies have demonstrated that ABCA1 may exert anticancer effects 1. Introduction through cellular cholesterol efflux, which has been attracting increasing attention in association with prostate cancer. The Prostate cancer is a common malignancy among men in aim of the present review was to focus on the current views Western countries; however, a sharp increase in its morbidity on prostate cancer progression and the various functions and mortality was recently observed in several Asian countries, of ABCA1, in order to provide new therapeutic targets for including China (1). Patients with aggressive pathological prostate cancer. characteristics are at increased risk for tumor progression and metastasis, even following radical treatment. Furthermore, these characteristics are commonly found in tumors from patients who succumb to prostate cancer. Cholesterol homeostasis is crucial for cell function and survival, whereas dysregulation of cholesterol homeostasis is known to be associated with multiple cancers, including prostate cancer (2), and altered lipid metabolism is increasingly recognized as a hallmark of prostate cancer cells (3). In fact, lethal prostate cancers exhibit higher Correspondence to: Dr Jian Tu, Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center expression of squalene monooxygenase, which is the second for Molecular Target New Drug Study, University of South China, rate-limiting enzyme of cholesterol synthesis (4). Moreover, 28 Changsheng Road, Hengyang, Hunan 421001, P.R. China low serum cholesterol levels have been found in prostate cancer E-mail: [email protected] patients, suggesting that cholesterol may accumulate in tumor tissue. Compared with normal prostate cells, prostate tumor Abbreviations: ABC, ATP‑binding cassette; LDL, low‑density cells exhibit increased levels of intracellular cholesterol precur- lipoprotein; apoA‑I, apolipoprotein A‑I; TGF‑β, transforming sors, with loss of ABCA1‑mediated cholesterol efflux (5). growth factor‑β; JAK2, Janus kinase 2; STAT3, signal ATP-binding cassette (ABC) transporters are trans- transducer and activator of transcription 3; HDL, high-density membrane proteins responsible for the transfer of various lipoprotein; LXR, liver X receptor; MDR, multidrug resistance; substrates through extracellular and intracellular membranes. PI3K, phosphoinositide 3-kinase; ERK, extracellular signal-regulated kinase; P-gp, P-glycoprotein; MRP, multidrug The ABC‑type transporters act as gatekeepers by allowing or resistance‑associated protein; EGFR, epidermal growth factor limiting the entrance of a wide variety of substrates across receptor cellular membranes (6). A total of 51 ABC transporter genes have been identified and are grouped into seven subfamilies, Key words: ATP-binding cassette transporter A1, prostate cancer, namely A-G, based on their phylogenetic distance (7). The cholesterol physiological importance of ABCA subfamily proteins is underscored by their association with various inher- ited diseases. Examples of ABC A-subfamily disorders include Tangier disease (ABCA1), Alzheimer's disease 10 XIONG et al: ABC TRANSPORTER A1: A PROMISING THERAPY TARGET FOR PROSTATE CANCER (ABCA2/ABCA7), Stargardt's disease (ABCR/ABCA4), efflux capacity (22). In addition, transforming growth factor harlequin-type ichthyosis (ABCA12) and others (8) (Table I). (TGF)‑β signaling plays a key role in prostate cancer occur- ABCA1, an ABC subfamily A exporter, mediates the cellular rence and maintenance of cancer stem cell characteristics. The efflux of phospholipids and cholesterol to the extracellular growth inhibitory effect of TGF‑β may be due to overexpres- acceptor apolipoprotein A-I (apoA-I) for generation of nascent sion of ABCA1 in prostate cancer cells (23). The expression of high-density lipoprotein (HDL) (9). The human ABCA1 has ABCA1 is associated with nuclear receptor of liver X receptor a length of 2,261 amino acids, and was found to contain two (LXR) and LXR forms a heterodimer with retinoid X receptor transmembrane domains (TMDs) (10). Each TMD is followed and regulates transcription of ABCA1 by binding to the DR-4 by a cytoplasmic region comprising one nucleotide-binding promoter element (24). Furthermore, TGF‑β may increase domain (NBD) and one small regulatory domain. The NBDs ABCA1 expression through activation of LXR signaling. It has and regulatory domains are the most highly conserved been demonstrated that LXR activation, with accompanying elements among the ABCA subfamily. The structure of upregulation of ABCA1 expression, may decrease cholesterol ABCA1 reveals a polar cluster on one side of TMD1 close to levels and reduce the growth of prostate cancer cell xenograft the intracellular boundary (11). The structure of the ABCA1 tumors in mice (25). Furthermore, LXR agonists have been presented herein represents a major step towards the mecha- shown to induce expression of ABCA1, inhibit tumor growth nistic understanding of ABCA1-mediated lipid export and and reduce progression to androgen independence in a xeno- nascent HDL biogenesis (12). ABCA1 has been shown to be graft model of prostate cancer (26). The antitumor effects of necessary for the synthesis of HDL by exporting cholesterol these compounds may involve a variety of mechanisms: Statins out of the cells (13). Functional ABCA1 mediates the expan- inhibit GTPases such as Ras and Rho family proteins via sion of the N‑terminus of apoA‑I on the cell surface, followed blocking protein prenylation and/or farnesylation, and LXR by the release of nascent HDL, which is the only path for agonists induce cell cycle arrest through upregulation of p27. elimination of cholesterol from the body (14). Two missense Conversely, intracellular cholesterol promotes prostate cancer mutations of human ABCA1 proteins linked to Tangier progression as a substrate for de novo androgen synthesis and disease and familial HDL deficiency were previously found through regulation of Akt signaling (22). to be associated with diminished cholesterol efflux activity, Hypermethylation of the ABCA1 promoter has been and the functionality of these ABCA1 mutants in terms of shown to silence ABCA1 expression and is associated tumor inhibition and cholesterol efflux was tested in prostate with high‑grade prostate cancer (27). The interaction of cancer cells lacking endogenous ABCA1 expression (15). Over apoA‑I with ABCA1 activates the signaling molecule Janus 50 mutations in the ABCA1 gene were recently identified. The kinase 2 (JAK2), which optimizes the cholesterol efflux human ABCA1 has been shown to be closely associated with activity of ABCA1 by phosphorylation (28). ABCA1-mediated the development of various human cancers, including prostate, JAK2 activation also activates signal transducer and activator colon and breast cancer (16-18). Prostate cancer patients with of transcription 3 (STAT3), which significantly attenuates the higher serum low‑density lipoprotein (LDL) levels exhibited expression of proinflammatory cytokines in macrophages. significantly shorter overall survival. Low ABCA1 expression The anti‑inflammatory effects of the apoA‑I/ABCA1/STAT3 has also been associated with shorter survival in patients with pathway, however, is dependent on the activity of suppressor prostate cancer. This may be explained by the use of lipid of cytokine signaling 3. Taken together, these findings as an energy source during growth and metastasis of pros- suggest that the interaction of apoA-I/ABCA1 activates tate cancer cells. ABCA1 has been shown to play a critical cholesterol efflux and STAT3 branching pathways to synergis- role in the synthesis of HDL particles by exporting cellular tically inhibit inflammation in macrophages (29). It was also cholesterol (19,20). demonstrated that the apoA‑I/ABCA1 interaction with the Considering these findings, further investigation into JAK2/STAT3 pathway to inhibit macrophage inflammatory ABCA1 as a tumor suppressor in prostate cancer is required. responses is independent of ABCA1 lipid transport function. We herein review the role of ABCA1 in prostate cancer and the ABCA1 mutation carriers also exhibit an increased inci- ongoing research on its association with cancer proliferation, dence of systemic and plaque inflammation (30). It has been
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