Enhancement of the Antitumor Effect of Methotrexate on Colorectal Cancer Cells via Lactate Calcium Salt Targeting Methionine Metabolism. (19th May 2017)

• Record Type: Journal Article
• Authors: Jo, Young-Kwon; Park, Min Hee; Choi, Hyunju; Lee, HooKeun; Park, Jong-Moon; Sim, Jae Jun; Chang, Chonghwan; Jeong, Keun-Yeong; Kim, Hwan Mook
• Is Part Of: Nutrition and cancer. Volume 69:Number 4(2017)
• Page Start: 663
• Page End: 673
• Publication Date: 2017-05-19
• Subjects: Cancer -- Periodicals; Nutrition -- Periodicals; Cancer; Nutrition; Periodicals; 616.9940654
• DOI: 10.1080/01635581.2017.1299879
• Languages: English
• ISSNs: 0163-5581

Abstract

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.