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

JaeJin An; Heon Seok; Eun-Mi Ha

doi:10.1007/s12275-021-0562-5

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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: JaeJin An ¹, Heon Seok ², Eun-Mi Ha ³; Journal of Microbiology 2021;59(2):202-216.
DOI: https://doi.org/10.1007/s12275-021-0562-5
Published online: February 1, 2021

¹Medical Convergence Materials Commercialization Center, Gyeongsan 38408, Republic of Korea, ²Korea Brain bank, Korea Brain Research Institute, Daegu 41062, Republic of Korea, ³Department of Pharmacology, College of Pharmacy, Catholic University of Daegu, Gyeongsan 38430, Republic of Korea

Corresponding author: Eun-Mi Ha , Tel: +82-53-850-3612,

Received: 2 November 2020 • Revised: 16 December 2020 • Accepted: 21 December 2020

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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.

Keywords: Lactobacillus plantarum, 5-FU resistant, colorectal cancer cell, GABA, GABAergic system, cAMP-dependent signal pathway, metastasis

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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

J. Microbiol. 2021;59(2):202-216. Published online February 1, 2021

DOI: https://doi.org/10.1007/s12275-021-0562-5

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