Extracellular vesicles derived from Lactobacillus plantarum restore chemosensitivity through the PDK2-mediated glucose metabolic pathway in 5-FU-resistant colorectal cancer cells

JaeJin An; Eun-Mi Ha

doi:10.1007/s12275-022-2201-1

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Extracellular vesicles derived from Lactobacillus plantarum restore chemosensitivity through the PDK2-mediated glucose metabolic pathway in 5-FU-resistant colorectal cancer cells: JaeJin An ¹, Eun-Mi Ha ²; Journal of Microbiology 2022;60(7):735-745.
DOI: https://doi.org/10.1007/s12275-022-2201-1
Published online: July 4, 2022

¹Medical Convergence Textile Center, Gyeongbuk Techno Park, Gyeongsan 38408, Republic of Korea, ²College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Republic of Korea

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

Received: 9 May 2022 • Revised: 25 May 2022 • Accepted: 27 May 2022

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Abstract

Metabolic abnormalities are one of the main hallmarks of cancer and are associated with chemoresistance. Therefore, targeting the metabolic reprogramming of cancer cells has the potential to overcome chemoresistance. Probiotic-derived extracellular vesicles (EVs) play important roles in biological function and intracellular communication. However, the inhibitory effect of Lactobacillus plantarum-derived EVs (LpEVs) on colorectal cancer (CRC) cells has not yet been elucidated. This study clearly revealed that increased glycolysis in 5-fluorouracil (5-FU)-resistant CRC cells (CRC/5FUR) is directly related to chemoresistance and that the metabolic shift reversed by LpEVs inhibits cancer cell proliferation and eventually leads to apoptosis. Pyruvate dehydrogenase kinase 2 (PDK2), one of the crucial enzymes for enhancing glycolysis, was upregulated in CRC/5FUR cells. In our study, LpEVs sensitized CRC/5FUR cells to 5-FU by attenuating PDK2 expression in p53-p21-dependent metabolic signaling, thereby circumventing 5-FU resistance. We demonstrated the effect of cellular responses to 5-FU by modifying the PDK2 expression level in both 5-FU-sensitive parental CRC and 5- FU resistant CRC cell lines. Finally, we revealed that the PDK2 signaling pathway can potentially be targeted using LpEVs treatment to overcome chemoresistant CRC, thereby providing a potential strategy for CRC treatment by intervening in tumor metabolism.

Keywords: Lactobacillus plantarum, extracellular vesicles, 5-FU, chemoresistance, colorectal cancer, glucose metabolism, PDK2

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Extracellular vesicles derived from Lactobacillus plantarum restore chemosensitivity through the PDK2-mediated glucose metabolic pathway in 5-FU-resistant colorectal cancer cells

J. Microbiol. 2022;60(7):735-745. Published online July 4, 2022

DOI: https://doi.org/10.1007/s12275-022-2201-1

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