- Extracellular vesicles derived from Lactobacillus plantarum restore chemosensitivity through the PDK2-mediated glucose metabolic pathway in 5-FU-resistant colorectal cancer cells
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JaeJin An , Eun-Mi Ha
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J. Microbiol. 2022;60(7):735-745. Published online July 4, 2022
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DOI: https://doi.org/10.1007/s12275-022-2201-1
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Abstract
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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.
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Citations
Citations to this article as recorded by 
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Kusuma Kandati, Viswanath Buddolla, John Sushma Nannepaga Medicine in Microecology.2026; 27: 100160. CrossRef - Unveiling the tumor microenvironment in colorectal cancer therapeutic resistance
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Mohaddeseh Fathi, Sheyda Khalilian, Atefeh Bijanvand, Hamid Abedinlou, Soudeh Ghafouri-Fard Current Microbiology.2026;[Epub] CrossRef - The Role of Bacterial Outer Membrane Vesicles in Tumor Development: Facts, Potential Applications and Future Perspectives
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Ying He, Ziyang Yu, Wanyu Zhang, Xinke Nie, Junhua Xie Food Bioscience.2026; 79: 108712. CrossRef - Gut microbiome-shaped chemotherapy responses across cancer types: mechanisms of resistance, biomarkers, and targeted interventions
Ting Shao, Minghui Li, Shaolin Li, Jie Pu, Chunsheng Li, Changgang Guo Frontiers in Immunology.2026;[Epub] CrossRef - Effect of probiotic extracellular vesicles and their applications on health and disease
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Joshua Tobias, Stefan Heinl, Kristina Dendinovic, Ajša Ramić, Anna Schmid, Catherine Daniel, Ursula Wiedermann Immunology Letters.2025; 272: 106971. CrossRef - Probiotic Lactobacillus‐Derived Extracellular Vesicles: Insights Into Disease Prevention and Management
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Ke Peng, Lina Liu, Shujun Gao World Journal of Microbiology and Biotechnology.2025;[Epub] CrossRef - A critical evaluation of methodological and mechanistic insights on probiotic-derived extracellular vesicles
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Extracellular Vesicles from
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PC-H1 Inhibit HIF-1α-Mediated Glycolysis of Colon Cancer
Yangqian Shi, Chunliang Zhang, Wanyu Cao, Luyi Li, Kaili Liu, Hanyue Zhu, Fikadu Balcha, Yong Fang Future Microbiology.2024; 19(3): 227. CrossRef - Role of probiotic extracellular vesicles in inter-kingdom communication and current technical limitations in advancing their therapeutic utility
Rahul Sanwlani, Kyle Bramich, Suresh Mathivanan Extracellular Vesicles and Circulating Nucleic Acids.2024; : 609. CrossRef - Beneficial microbiome and diet interplay in early-onset colorectal cancer
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Sona Ciernikova, Aneta Sevcikova, Michal Mego American Journal of Physiology-Cell Physiology.2024; 327(6): C1433. CrossRef - Lactobacillus plantarum Metabolites Elicit Anticancer Effects by Inhibiting Autophagy-Related Responses
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- Lactobacillus plantarum-derived metabolites sensitize the tumorsuppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells
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Hye-Ju Kim , JaeJin An , Eun-Mi Ha
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J. Microbiol. 2022;60(1):100-117. Published online December 29, 2021
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DOI: https://doi.org/10.1007/s12275-022-1533-1
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1,027
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5
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40
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Abstract
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A critical obstacle to the successful treatment of colorectal
cancer (CRC) is chemoresistance. Chemoresistant CRC cells
contribute to treatment failure by providing a mechanism
of drug lethargy and modifying chemoresistance-associated
molecules. The gut microbiota provide prophylactic and therapeutic
effects by targeting CRC through anticancer mechanisms.
Among them, Lactobacillus plantarum contributes
to the health of the host and is clinically effective in treating
CRC. This study confirmed that 5-fluorouracil (5-FU)-resistant
CRC HCT116 (HCT116/5FUR) cells acquired butyrateinsensitive
properties. To date, the relationship between 5-
FU-resistant CRC and butyrate resistance has not been elucidated.
Here, we demonstrated that the acquisition of butyrate
resistance in HCT116/5FUR cells was strongly correlated
with the inhibition of the expression and function of
SMCT1, a major transporter of butyrate in colonocytes. L.
plantarum-cultured cell-free supernatant (LP) restored the
functional expression of SMCT1 in HCT116/5FUR cells, leading
to butyrate-induced antiproliferative effect and apoptosis.
These results suggest that LP has a synergistic effect on the
SMCT1/butyrate-mediated tumor suppressor function and
is a potential chemosensitizer to overcome dual 5-FU and butyrate
resistance in HCT116 cells.
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JaeJin An, Eun-Mi Ha Journal of Microbiology.2022; 60(7): 735. CrossRef
- GABA-producing Lactobacillus plantarum inhibits metastatic properties and induces apoptosis of 5-FU-resistant colorectal cancer cells via GABAB receptor signaling
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JaeJin An , Heon Seok , Eun-Mi Ha
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J. Microbiol. 2021;59(2):202-216. Published online February 1, 2021
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DOI: https://doi.org/10.1007/s12275-021-0562-5
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59
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Abstract
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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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- 1Medical Convergence Materials Commercialization Center, Gyeongsan
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JaeJin An , Eun-Mi Ha
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J. Microbiol. 2020;58(11):967-977. Published online October 30, 2020
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DOI: https://doi.org/10.1007/s12275-020-0375-y
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Abstract
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Lactobacillus plantarum-derived metabolites (LDMs) increase
drug sensitivity to 5-FU and antimetastatic effects in 5-FUresistant
colorectal cancer cells (HCT-116/5FUR). In this
study, we evaluated the effects of LDMs on the regulation of
genes and proteins involved in HCT-116/5-FUR cell proliferation
and metastasis. HCT-116/5-FUR cells showed high
metastatic potential, significantly reduced tight junction (TJ)
integrity, including increased migration and paracellular permeability,
and upregulation of claudin-1 (CLDN-1). The genetic
silencing of CLDN-1 increased the sensitivity of HCT-
116/5FUR to 5-FU and inhibited its metastatic potential by
regulating the expression of epithelial-mesenchymal transition
(EMT) related genes. Co-treatment of HCT-116/5FUR
with LDMs and 5-FU suppressed chemoresistant and metastatic
behavior by downregulating CLDN-1 expression. Finally,
we designed LDMs-based therapeutic strategies to treatment
for metastatic 5-FU-resistant colorectal cancer cells. These
results suggested that LDMs and 5-FU cotreatments can synergistically
target 5-FU-resistant cells, making it a candidate
strategy to overcome 5-FU chemoresistance improve anticancer
drug efficacy.
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