title: Pyruvate kinase isoenzyme M2 is a therapeutic target of gemcitabine-resistant pancreatic cancer cells.
abstract: Despite its wide use as a first-line therapeutic agent, gemcitabine has shown limited efficacy in advanced pancreatic cancer due to chemoresistance by as yet unidentified mechanisms. Our goal here was to identify molecular features involved in gemcitabine chemoresistance. Pyruvate kinase M2 (PKM2), a key enzyme of aerobic glycolysis, has recently emerged as an important therapeutic target for cancer treatment. It is involved in the metabolic reprogramming of cancer cells and has previously unexpected non-metabolic functions that are heavily involved in tumor growth and survival. Herein, we report that the chemoresistance of pancreatic cancer to gemcitabine was dependent on PKM2 expression and its non-metabolic function. Knocking-down of PKM2 significantly enhanced gemcitabine-induced cell apoptosis through the activation of caspase 3/7 and PARP cleavage, and this inhibitory activity was associated with p38-mediated activation of p53 phosphorylation at serine 46. Our findings support the potential of PKM2 as a novel target for gemcitabine chemoresistance and suggest the feasibility of combining gemcitabine and PKM2 inhibition for the improved chemotherapy of pancreatic cancer.
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, South Korea.
authors.forename: Dong Joon
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, South Korea.
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, WA, DC 20037, USA.
authors.forename: Min Gu
authors.initials: MG
authors.lastname: Kang
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, South Korea; Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, South Korea.
authors.forename: Yeon-Mi
authors.initials: YM
authors.lastname: You
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, South Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, South Korea; Department of Medical-BioScience, Soonchunhyang University, Asan 336-745, South Korea.
authors.forename: Han
authors.initials: H
authors.lastname: Koo
authors.affiliation: Epigenomics Research Center, Genome Institute, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, South Korea.
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Mi-Ju
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, South Korea.
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.affiliation: Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea.
authors.forename: Kyong Bun
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, South Korea.
authors.forename: Ja-June
authors.initials: JJ
authors.lastname: Jang
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, South Korea. Electronic address: kpark@kribb.re.kr.
authors.forename: Kyung Chan
authors.initials: KC
authors.lastname: Park
authors.affiliation: Genome Structure Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 305-806, South Korea; Department of Functional Genomics, Korea University of Science and Technology, Daejeon 305-350, South Korea. Electronic address: yeomyi@kribb.re.kr.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D003841:Deoxycytidine; D008565:Membrane Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013963:Thyroid Hormones; D000093542:Gemcitabine; D000097810:Thyroid Hormone-Binding Proteins
keywords: Apoptosis; Gemcitabine; PKM2; Pancreatic cancer; p53