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GABA-producing Lactobacillus plantarum inhibits metastatic properties and induces apoptosis of 5-FU-resistant colorectal cancer cells via GABAB receptor signaling

  • Microbial Pathogenesis and Host-Microbe Interaction
  • Published:
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Abstract

5-Fluorouracil (5-FU) is an essential drug in systemic chemotherapy treatments for colorectal cancer (CRC). Despite the development of several treatment strategies over the past decades, the patient benefits of 5-FU-based therapies have been compromised by the development of chemoresistance. Differences in treatment responses among CRC patients may be due to genetic and epigenetic factors unique to individuals. Therefore, important factors for realizing personalized medicine are to accurately understand the causes and mechanisms of drug resistance to 5-FU-based therapies and to identify and validate prognostic biomarkers. Gut microbes that interact directly with the host contribute to human health and cancer control. Lactobacillus plantarum, in particular, has the potential to be a therapeutic agent by producing bioactive compounds that may benefit the host. Here, we investigated the gamma-aminobutyric acid (GABA) and GABAB receptor (GABABR)-dependent signaling pathway as a treatment option for 5-FU-resistant HT-29 cells. GABA-producing L. plantarum activates anti-proliferative, anti-migration, and anti-invasion effects against 5-FU-resistant HT-29 cells. The inhibitory effects of GABA-producing L. plantarum are mediated via GABABR. Activated GABABR induces apoptosis through the inhibition of cAMP-dependent signaling pathways and cellular inhibitor of apoptosis protein 2 (cIAP2) expression. Thus, the GABAergic system has potential in 5-FU-resistant HT-29 cells as a predictive biomarker. In addition, GABA-producing L. plantarum is promising as an adjuvant treatment for 5-FU-resistant CRC, and its intervention in neurobiological signaling imply new possibilities for chemoprevention and the treatment of colon cancer-related diseases.

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Acknowledgments

This research was funded by the National Research Foundation of Korea (NRF2016R1D1A1B03934262).

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Authors and Affiliations

  1. Medical Convergence Materials Commercialization Center, Gyeongsan, 38408, Republic of Korea

    JaeJin An

  2. Korea Brain bank, Korea Brain Research Institute, Daegu, 41062, Republic of Korea

    Heon Seok

  3. Department of Pharmacology, College of Pharmacy, Catholic University of Daegu, Gyeongsan, 38430, Republic of Korea

    Eun-Mi Ha

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  1. JaeJin An
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Correspondence to Eun-Mi Ha.

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An, J., Seok, H. & Ha, EM. GABA-producing Lactobacillus plantarum inhibits metastatic properties and induces apoptosis of 5-FU-resistant colorectal cancer cells via GABAB receptor signaling. J Microbiol. 59, 202–216 (2021). https://doi.org/10.1007/s12275-021-0562-5

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