ABCC3 is a novel target for the treatment of pancreatic cancer
ABCC3 is a novel target for the treatment of pancreatic cancer
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DOI：
10.1016/j.jbior.2019.04.004
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发表时间：
2019-08-01
影响因子：
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通讯作者：
Falasca, Marco
中科院分区：
文献类型：
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作者：
Adamska, Aleksandra;Ferro, Riccardo;Falasca, Marco
胰腺导管腺癌（PDAC）是一种非常侵袭性的疾病，缺乏有效的治疗方法，使PDAC患者预后不良。PDAC患者的预期寿命在过去几十年中没有发生显著变化，五年生存率仅为8%。为了解决这一未满足的需求，必须确定新的药理学靶点进行临床干预。ATP结合盒（ABC）转运蛋白在不同的癌症类型中经常过表达，是导致化疗耐药性的主要机制之一。然而，ABC转运蛋白在肿瘤发生中更直接的作用尚未得到广泛研究。在这里，我们表明ABCC 3（ABC亚家族C成员3;以前称为MRP 3）在PDAC细胞系和临床样本中过表达。我们证明ABCC 3表达受突变型p53通过miR-34调节，并且转运蛋白通过生物活性脂质溶血磷脂酰肌醇（LPI）的转运驱动PDAC进展。通过基因敲低破坏ABCC 3功能可降低体外和体内胰腺癌细胞生长。从机制上讲，我们证明ABCC 3的敲低通过抑制STAT 3和HIF 1 α信号通路来减少细胞增殖，这些信号通路以前被证明是PDAC进展的关键调节因子。总的来说，我们的研究结果将ABCC 3确定为PDAC治疗中的新的和有前途的靶点。
Pancreatic Ductal Adenocarcinoma (PDAC) is a very aggressive disease, lacking effective therapeutic 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 expression 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 HIF1 alpha signalling pathways, previously been shown to be key regulators of PDAC progression. Collectively, our results identify ABCC3 as a novel and promising target in PDAC therapy.