Microcystin LR Shows Cytotoxic Activity Against Pancreatic Cancer Cells Expressing the Membrane OATP1B1 and OATP1B3 Transporters.
Microcystin-LR (MC-LR) is a cyanobacterial cyclopeptide, known for its unique ability to cause acute liver injury. Its cellular uptake is facilitated by specific transmembrane organic anion-transporting polypeptides (OATPs) specifically OATP1B1 and 1B3. The objective of the present study was to investigate the expression of OATPs 1A2, 1B1 and 1B3 in pancreatic cancer cell lines BxPC-3 and MIA PACA-2 and assess their role in MC-LR-mediated cytotoxicity by using the novel xCELLigence system and flow cytometry. OATP1B1 and 1B3 were found to be expressed in both cell lines at both the mRNA and protein levels. The cytotoxic effects of MC-LR were proportionally related to the expression of these transporters. Moreover the cytotoxic potency of MC-LR was found superior to gemcitabine. Based on the expression of the organic anion transporting polypeptides 1B1 and 1B3 in pancreatic carcinoma tissue and cell lines and the potent cytotoxicity induced by MC-LR in vitro, we propose that this molecule could be held as structural basis for the development of novel targeted-compounds against pancreatic cancer.
Molecular Oncology Laboratories, Oxford University, Department of Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, U.K. Human Cancer Biobank Center, University of Ioannina, Ioannina, Greece valentinos.kounnis@oncology.ox.ac.uk.
Valentinos
V
Kounnis
Department of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Ioannina, Greece.
Georgios
G
Chondrogiannis
Laboratory of Biological Chemistry, Medical School, University of Ioannina, Ioannina, Greece.
Michalis D
MD
Mantzaris
Human Cancer Biobank Center, University of Ioannina, Ioannina, Greece Department of Chemistry, University of Ioannina, Ioannina, Greece.
Andreas G
AG
Tzakos
Department of Materials Science and Engineering, University of Ioannina, Ioannina, Greece.
Demosthenes
D
Fokas
Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Nikolaos A
NA
Papanikolaou
Department of Anatomy-Histology-Embryology, Medical School, University of Ioannina, Ioannina, Greece.
Vasiliki
V
Galani
Human Cancer Biobank Center, University of Ioannina, Ioannina, Greece.
Ioannis
I
Sainis
Human Cancer Biobank Center, University of Ioannina, Ioannina, Greece Medical School, University of Ioannina, Ioannina, Greece.
Evangelos
E
Briasoulis
D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D027381:Liver-Specific Organic Anion Transporter 1; D008387:Marine Toxins; D052998:Microcystins / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D008387:Marine Toxins; D052998:Microcystins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D010749:Phosphoprotein Phosphatases; C057862:cyanoginosin LR
OATPs; Organic anion-transporting polypeptides; cancer treatment; drug development; microcystin-LR; pancreatic cancer; targeted-therapy