Kong Su Chii, Nøhr-Nielsen Asbjørn, Zeeberg Katrine, Reshkin Stephan Joel, Hoffmann Else Kay, Novak Ivana, Pedersen Stine Falsig
From the *Faculty of Science, Section for Cell and Developmental Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark; †Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy; and ‡Faculty of Science, Section for Molecular Integrative Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Pancreas. 2016 Aug;45(7):1036-47. doi: 10.1097/MPA.0000000000000571.
Novel treatments for pancreatic ductal adenocarcinoma (PDAC) are severely needed. The aim of this work was to explore the roles of H-lactate monocarboxylate transporters 1 and 4 (MCT1 and MCT4) in PDAC cell migration and invasiveness.
Monocarboxylate transporter expression, localization, activity, and function were explored in human PDAC cells (MIAPaCa-2, Panc-1, BxPC-3, AsPC-1) and normal human pancreatic ductal epithelial (HPDE) cells, by quantitative polymerase chain reaction, immunoblotting, immunocytochemistry, lactate flux, migration, and invasion assays.
MCT1 and MCT4 (messenger RNA, protein) were robustly expressed in all PDAC lines, localizing to the plasma membrane. Lactate influx capacity was highest in AsPC-1 cells and lowest in HPDE cells and was inhibited by the MCT inhibitor α-cyano-4-hydroxycinnamate (4-CIN), MCT1/MCT2 inhibitor AR-C155858, or knockdown of MCT1 or MCT4. PDAC cell migration was largely unaffected by MCT1/MCT2 inhibition or MCT1 knockdown but was reduced by 4-CIN and by MCT4 knockdown (BxPC-3). Invasion measured in Boyden chamber (BxPC-3, Panc-1) and spheroid outgrowth (BxPC-3) assays was attenuated by 4-CIN and AR-C155858 and by MCT1 or MCT4 knockdown.
Human PDAC cells exhibit robust MCT1 and MCT4 expression and partially MCT1- and MCT4-dependent lactate flux. PDAC cell migration is partially dependent on MCT4; and invasion, on MCT1 and MCT4. Inhibition of MCT1 and MCT4 may have clinical relevance in PDAC.
胰腺导管腺癌（PDAC）急需新型治疗方法。本研究旨在探讨单羧酸转运蛋白1和4（MCT1和MCT4）在PDAC细胞迁移和侵袭中的作用。
通过定量聚合酶链反应、免疫印迹、免疫细胞化学、乳酸通量、迁移和侵袭试验，研究人PDAC细胞（MIAPaCa-2、Panc-1、BxPC-3、AsPC-1）和正常人胰腺导管上皮（HPDE）细胞中单羧酸转运蛋白的表达、定位、活性和功能。
MCT1和MCT4（信使核糖核酸、蛋白质）在所有PDAC细胞系中均有强烈表达，定位于质膜。AsPC-1细胞的乳酸流入能力最高，HPDE细胞最低，且被MCT抑制剂α-氰基-4-羟基肉桂酸（4-CIN）、MCT1/MCT2抑制剂AR-C155858或MCT1或MCT4的敲低所抑制。MCT1/MCT2抑制或MCT1敲低对PDAC细胞迁移影响不大，但4-CIN和MCT4敲低（BxPC-3）可使其降低。在Boyden小室（BxPC-3、Panc-1）和球体生长（BxPC-3）试验中检测的侵袭被4-CIN和AR-C155858以及MCT1或MCT4敲低所减弱。
人PDAC细胞表现出强烈的MCT1和MCT4表达以及部分依赖MCT1和MCT4的乳酸通量。PDAC细胞迁移部分依赖于MCT4；侵袭则依赖于MCT1和MCT4。抑制MCT1和MCT4可能在PDAC中具有临床意义。
