| Title | Extracellular vesicles derived from Lactobacillus plantarum restore chemosensitivity through the PDK2-mediated glucose metabolic pathway in 5-FU-resistant colorectal cancer cells |
|---|---|
| Author | JaeJin An1 and Eun-Mi Ha2* |
| Address | 1Medical Convergence Textile Center, Gyeongbuk Techno Park, Gyeongsan 38408, Republic of Korea, 2College of Pharmacy, Daegu Catholic University, Gyeongsan 38430, Republic of Korea |
| Bibliography | Journal of Microbiology, 60(7),735-745, 2022, |
| DOI | 10.1007/s12275-022-2201-1 |
| Key Words | Lactobacillus plantarum, extracellular vesicles, 5-FU, chemoresistance, colorectal cancer, glucose metabolism, PDK2 |
| 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. |