Objectives: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
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.
Received for publication April 4, 2015; accepted October 27, 2015.
Address correspondence to: Stine Falsig Pedersen, PhD, Department of Biology, University of Copenhagen, Universitetsparken 13, DK-2100 Copenhagen, Denmark (e-mail: firstname.lastname@example.org).
This study was supported by the Marie Curie Initial Training Network IonTraC (grant agreement no. 289648) Kirsten and Freddy Johansens Fond, and the Hartmann Foundation.
The authors declare no conflict of interest.
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