title: Enhancement of the Antitumor Effect of Methotrexate on Colorectal Cancer Cells via Lactate Calcium Salt Targeting Methionine Metabolism.
abstract: Methionine (Met) is involved in one-carbon de novo nucleotide synthesis and is an essential amino acid for cell survival. The impact of lactate calcium salt (CaLa) on the Met metabolism was investigated to evaluate the enhanced antitumor effect of methotrexate (MTX) on colorectal cancer (CRC) cells. Met dependency relating to homocysteine (Hcy) and betaine was investigated in human CRC cells (HCT-116 and HT-29) using a viability assay and liquid chromatography-mass spectrometry. Expression of betaine transporter-1 (BGT-1) following treatment with MTX alone or with CaLa was determined by Western blot. Enhanced antitumor effect due to malfunction of Met synthesis was confirmed. CRC cell viability decreased in Met-restricted medium, but was maintained after Hcy and betaine treatment while overcoming Met restriction. BGT-1 expression was downregulated following the treatment of dose-increased CaLa, whereas there was no effect on BGT-1 expression after MTX treatment. CaLa in combination with MTX induced reduced Met synthesis when CRC cell viability was reduced. The results indicated that CaLa-mediated BGT-1 downregulation inhibits Met synthesis by disrupting betaine homeostasis. CaLa raised the antitumor effect of MTX via secondary role in the inhibition of the de novo nucleotide synthesis. Combination therapy of MTX and CaLa could maximize the effectiveness of CRC treatment.
authors.affiliation: a Gachon Institute of Pharmaceutical Science , Gachon University , Incheon , Republic of Korea.
authors.forename: Young-Kwon
authors.initials: YK
authors.lastname: Jo
authors.affiliation: a Gachon Institute of Pharmaceutical Science , Gachon University , Incheon , Republic of Korea.
authors.forename: Min Hee
authors.initials: MH
authors.lastname: Park
authors.affiliation: a Gachon Institute of Pharmaceutical Science , Gachon University , Incheon , Republic of Korea.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Choi
authors.affiliation: a Gachon Institute of Pharmaceutical Science , Gachon University , Incheon , Republic of Korea.
authors.forename: HooKeun
authors.initials: H
authors.lastname: Lee
authors.affiliation: a Gachon Institute of Pharmaceutical Science , Gachon University , Incheon , Republic of Korea.
authors.forename: Jong-Moon
authors.initials: JM
authors.lastname: Park
authors.affiliation: a Gachon Institute of Pharmaceutical Science , Gachon University , Incheon , Republic of Korea.
authors.forename: Jae Jun
authors.initials: JJ
authors.lastname: Sim
authors.affiliation: b Oncometplus Pharmaceuticals Co. R&D Division , Incheon , Republic of Korea.
authors.forename: Chonghwan
authors.initials: C
authors.lastname: Chang
authors.affiliation: b Oncometplus Pharmaceuticals Co. R&D Division , Incheon , Republic of Korea.
authors.forename: Keun-Yeong
authors.initials: KY
authors.lastname: Jeong
authors.affiliation: a Gachon Institute of Pharmaceutical Science , Gachon University , Incheon , Republic of Korea.
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001622:Betaine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D017610:Calcium Compounds / Q000008:administration & dosage / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D050485:GABA Plasma Membrane Transport Proteins; D045325:HCT116 Cells / Q000187:drug effects; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D007773:Lactates / Q000008:administration & dosage / Q000494:pharmacology; D008715:Methionine / Q000378:metabolism*; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology; D058990:Molecular Targeted Therapy
chemical_list: D000964:Antimetabolites, Antineoplastic; D017610:Calcium Compounds; D002352:Carrier Proteins; D050485:GABA Plasma Membrane Transport Proteins; D007773:Lactates; C072207:betaine plasma membrane transport proteins; C110051:calcium lactate; D001622:Betaine; D008715:Methionine; D008727:Methotrexate