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γ-Aminobutyric acid inhibits the proliferation and increases oxaliplatin sensitivity in human colon cancer cells

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Tumor Biology

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.

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 81071680 and 81272280), Shanghai Pujiang Outstanding Young Scientist Project.

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Authors and Affiliations

  1. The Department of Food Science and Engineering, School of Agriculture and Biology, Shanghai Jiaotong University, Shanghai, 200240, China

    Lihua Song, Ying Xiong, Jing Jiang & Yao Zhang

  2. Department of Laboratory Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China

    Aiying Du, Zhaofeng Tian & Hongli Yan

Authors
  1. Lihua Song
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  2. Aiying Du
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  3. Ying Xiong
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  4. Jing Jiang
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  5. Yao Zhang
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  6. Zhaofeng Tian
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  7. Hongli Yan
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Corresponding author

Correspondence to Hongli Yan.

Additional information

Lihua Song, Aiying Du,·and Ying Xiong contributed equally to this work.

Electronic supplementary material

Supplementary Fig. 1

Images showing the morphology of migrated or invaded SW620 cells. SW620 cells were planted in the wells of 24-well Transwell chambers and treated with GABA as described in the “Materials and methods” section. Twenty-four hours after treatment, images were obtained by using under an Olympus IX73 Phase Contrast Microscope (Olympus Corporation, Tokyo, Japan). Images in the left panel (a, c, e, g) were magnified on the right (b, d, f, h), respectively. Scale bar 1 mm (DOCX 294 kb)

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Song, L., Du, A., Xiong, Y. et al. γ-Aminobutyric acid inhibits the proliferation and increases oxaliplatin sensitivity in human colon cancer cells. Tumor Biol. 37, 14885–14894 (2016). https://doi.org/10.1007/s13277-016-5367-5

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  • DOI: https://doi.org/10.1007/s13277-016-5367-5

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