title: γ-Aminobutyric acid inhibits the proliferation and increases oxaliplatin sensitivity in human colon cancer cells.
abstract: γ-Aminobutyric acid (GABA) is a natural non-protein amino acid, which broadly exists in many plant parts and is widely used as an ingredient in the food industry. In mammals, it is widely distributed in central nervous system and non-neural tissues. In addition to a primary inhibitory neurotransmitter in the central nervous system, endogenous GABA content has been found to be elevated in neoplastic tissues in colon cancer. However, the effect of extraneous GABA on colon cancer has rarely been reported. In this study, we found the inhibitory effects of GABA on the proliferation of colon cancer cells (CCCs). The amino acid also suppressed metastasis of SW480 and SW620 cells. To further study the correlated mechanism, we analyzed the changes in cell cycle distribution and found that GABA suppressed cell cycle progression through G2/M or G1/S phase. Furthermore, RNA sequencing analysis revealed GABA-induced changes in the mRNA expression of 30 genes, including EGR1, MAPK4, NR4A1, Fos, and FosB, in all the three types of CCC. Importantly, GABA enhanced the anti-tumor efficacy of oxaliplatin (OXA) in subcutaneous xenograft tumor model in nude mice. The data suggest that GABA inhibits colon cancer cell proliferation perhaps by attenuating EGR1-NR4A1 axis, EGR1-Fos axis, and by disrupting MEK-EGR1 signaling pathway. This work reveals the pharmacological value of GABA derived from food and suggests that exogenous GABA might play an auxiliary role in polychemotherapy of colon cancer.
authors.affiliation: The Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, 200240, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Laboratory Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Aiying
authors.initials: A
authors.lastname: Du
authors.affiliation: The Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, 200240, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: The Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, 200240, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: The Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, 200240, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Zhaofeng
authors.initials: Z
authors.lastname: Tian
authors.affiliation: Department of Laboratory Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China. hongliyan@smmu.edu.cn.
authors.forename: Hongli
authors.initials: H
authors.lastname: Yan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004357:Drug Synergism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009944:Organoplatinum Compounds; D016760:Proto-Oncogene Proteins c-fos; D000077150:Oxaliplatin; D005680:gamma-Aminobutyric Acid
keywords: Cell cycle; Cell proliferation; Colon cancer cell; GABA; Metastasis; RNA sequencing