title: PKM1 is involved in resistance to anti-cancer drugs.
abstract: Resistance to chemotherapy is a crucial problem in the clinical situation. To overcome this issue, many mechanisms of chemoresistance have been elucidated so far. However, this problem still has not been solved completely. In this study, we investigated the mechanism of chemoresistance from the view of cancer metabolism-related genes, especially focusing on the expression profile of pyruvate kinase muscle (PKM) isoforms, which are rate-limiting enzymes in cancer-specific metabolism (Warburg effect). Herein, we showed that PKM1, which promotes oxidative phosphorylation (OXPHOS), was commonly up-regulated in various chemoresistant cells. To clarify the functions of PKM1 in chemoresistance, we investigated effects of PKM1 expression in DLD-1 parental, 5-FU-resistant and oxaliplatin-resistant DLD-1 cells. The overexpression of PKM1 resulted in resistance of the parental cells to 5-FU and oxaliplatin. Moreover, gene-silencing of PKM1 induced apoptosis in these cells including the resistant cells by causing a decrease in the mitochondrial membrane potential. Furthermore, combination therapy using 5-FU or oxaliplatin with siR-PKM1 was also effective against the resistant cells. Our findings should lead to the development of new agents that can cancel the chemoresistance from the view of cancer energy metabolism.
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Department of General and Gastroenterological Surgery, Osaka Medical College, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan. Electronic address: sur144@osaka-med.ac.jp.
authors.forename: Kohei
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Miku
authors.initials: M
authors.lastname: Sakai
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Sugito
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuranaga
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Minami
authors.initials: M
authors.lastname: Kumazaki
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Department of Oncological Surgery, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Futamura
authors.affiliation: Department of Oncological Surgery, Gifu University School of Medicine, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Uchiyama
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000737:chemistry; D000077150:Oxaliplatin; D010085:Oxidative Phosphorylation; D010641:Phenotype; D016192:Resting Phase, Cell Cycle; D013963:Thyroid Hormones / Q000378:metabolism*; D014162:Transfection; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D005472:Fluorouracil; D008565:Membrane Proteins; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins
keywords: Anti-cancer drug; Chemoresistance; PKM1; PKM2; Warburg effect