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  • br Advances in Biological Regulation br journal homepage www

    2020-03-24


    Advances in Biological Regulation
    journal homepage: www.elsevier.com/locate/jbior
    ABCC3 is a novel target for the treatment of pancreatic cancer
    Aleksandra Adamskaa, Riccardo Ferrob, Rossano Lattanzioc, Emily Caponec, Alice Domenichinia, Verena Damianic, Giovanna Chiorinod, Begum Gokcen Akkayab, Kenneth J. Lintonb, Vincenzo De Laurenzia,c, Gianluca Salac,1, Marco Falascaa,b,∗,1
    a Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, 6102, Perth, WA, Australia b Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Blizard Institute, Centre for Cell Biology and Cutaneous Research, 4 Newark Street, London, E1 2AT, UK c Dipartimento di Scienze Mediche, Orali e Biotecnologiche, University "G. d'Annunzio" di Chieti-Pescara, Centro Studi sull'Invecchiamento, CeSI-MeT, Chieti, 66100, Italy d Cancer Genomics Laboratory, Fondazione Edo and Elvo Tempia, Biella, Italy
    Keywords:
    Pancreatic ductal adenocarcinoma
    ABC transporters
    ABCC3
    PDAC therapy
    STAT3
    Pancreatic Ductal Adenocarcinoma (PDAC) is a very aggressive disease, lacking effective ther-apeutic approaches and leaving PDAC patients with a poor prognosis. The life expectancy of PDAC patients has not experienced a significant change in the last few decades with a five-year survival rate of only 8%. To address this unmet need, novel pharmacological targets must be identified for clinical intervention. ATP Binding Cassette (ABC) transporters are frequently overexpressed in different cancer types and represent one of the major mechanisms responsible for chemoresistance. However, a more direct role for ABC transporters in tumorigenesis has not been widely investigated. Here, we show that ABCC3 (ABC Subfamily C Member 3; previously known as MRP3) is overexpressed in PDAC cell lines and also in clinical samples. We demonstrate that ABCC3 L-NAME hydrochloride is regulated by mutant p53 via miR-34 and that the transporter drives PDAC progression via transport of the bioactive lipid lysophosphatidylinositol (LPI). Disruption of ABCC3 function either by genetic knockdown reduces pancreatic cancer cell growth in vitro and in vivo. Mechanistically, we demonstrate that knockdown of ABCC3 reduce cell proliferation by inhibition of STAT3 and HIF1α signalling pathways, previously been shown to be key reg-ulators of PDAC progression. Collectively, our results identify ABCC3 as a novel and promising target in PDAC therapy.
    1. Introduction
    Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the Western world (Garrido-Laguna and Hidalgo, 2015). Lack of distinctive symptoms leading to late diagnosis, early metastatic spread and huge genetic and pheno-typical heterogeneity of PDAC contribute to its aggressive nature and high chemoresistance, making most therapies ineffective (Adamska et al., 2017, 2018; Falasca et al., 2016). Surgical resection represents a therapeutic option only for 15–20% of PDAC
    ∗ Corresponding author. Curtin University, Metabolic Signalling Group, School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, GPO Box U1987, PERTH, WA, 6845, Australia.
    E-mail address: [email protected] (M. Falasca).
    1 These authors jointly supervised this work.
    A. Adamska, et al. Advances in Biological Regulation xxx (xxxx) xxxx
    patients presenting with local or locally advanced disease (Michalski et al., 2007), the majority of whom unfortunately relapse. Radiation therapy and chemotherapy remain the only options for advanced and metastatic patients. However, this approach only marginally extends the overall survival (Vaccaro et al., 2015). Up until recently, gemcitabine was the main available, FDA-approved chemotherapeutic; however, it prolonged patient survival by only a few weeks (Burris et al., 1997). Currently, Abraxane (albumin-bound paclitaxel) and FOLFIRINOX are additionally applied as a standard-of-care therapy, providing modest improvement in survival rates but accompanied by a higher incidence of adverse effects (Conroy et al., 2011; Von Hoff et al., 2013). The high mutational heterogeneity and the plasticity of PDAC limit the options for the development of targeted therapies (Adamska et al., 2017; Borja-Cacho et al., 2008; Heinemann et al., 2000). There is a need, therefore, to identify novel pharmacological targets and develop more effective and safe therapeutic options for PDAC patients. ABC transporters have previously been linked with poor outcome in cancer and this has generally been attributed to chemoresistance (Gottesman et al., 2002; Hagmann et al., 2011). ABC transporters, par-ticularly ABCB1 (P-glycoprotein), ABCG2 (BCRP) and ABCC1 (MRP1) are capable of effluxing a wide variety of substrates, including drugs, across the plasma membrane, lowering their intracellular concentration. The majority of studies have therefore focused on the role of ABC transporters in drug resistance and on its reversal. However, the ability of ABC transporters to also efflux bioactive molecules that play essential roles in cancer progression, suggests a more direct, active contribution of ABC transporters to carci-nogenesis (Adamska and Falasca, 2018; Domenichini et al., 2018; Fletcher et al., 2010; Pineiro et al., 2011). In particular, signalling lipids such as phospholipids, which role in several malignancies including pancreatic cancer has been well documented (Suh and Cocco, 2016), were proposed as ABC transporters ligands. However, this area has been overlooked and the therapeutic potential of ABC transporter inhibition in counteracting PDAC progression has not yet been fully explored. Recently, we described the existence of an autocrine loop in which LPI (lysophosphatidylinositol)-activated GPR55 stimulates proliferation of PDAC cell lines that harbour p53 mutations (Ferro et al., 2018; Ruban et al., 2014). We showed that the blockade of LPI receptor- GPR55 significantly reduced disease progression in mouse models of PDAC. Considering their involvement in phospholipid efflux from cells (Tarling et al., 2013), we proposed that ABC transporters may mediate LPI transport in PDAC (Ruban et al., 2014).