Skip to main content
SpringerLink
Log in

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

  • Microbial Pathogenesis and Host-Microbe Interaction
  • Published:
Journal of Microbiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abbot, E.L., McCormack, J.G., Reynet, C., Hassall, D.G., Buchan, K.W., and Yeaman, S.J. 2005. Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells. FEBS J. 272, 3004–3014.

    Article  CAS  PubMed  Google Scholar 

  • Ahmadi Badi, S., Moshiri, A., Fateh, A., Rahimi Jamnani, F., Sarshar, M., Vaziri, F., and Siadat, S.D. 2017. Microbiota-derived extracellular vesicles as new systemic regulators. Front. Microbiol. 8, 1610.

    Article  PubMed  PubMed Central  Google Scholar 

  • An, J. and Ha, E.M. 2016. Combination therapy of Lactobacillus plantarum supernatant and 5-fluouracil increases chemosensitivity in colorectal cancer cells. J. Microbiol. Biotechnol. 26, 1490–1503.

    Article  CAS  PubMed  Google Scholar 

  • An, J. and Ha, E.M. 2020. Lactobacillus-derived metabolites enhance the antitumor activity of 5-FU and inhibit metastatic behavior in 5-FU-resistant colorectal cancer cells by regulating claudin-1 expression. J. Microbiol. 58, 967–977.

    Article  CAS  PubMed  Google Scholar 

  • An, J., Seok, H., and Ha, E.M. 2021. 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.

    Article  CAS  PubMed  Google Scholar 

  • Behzadi, E., Mahmoodzadeh Hosseini, H., and Imani Fooladi, A.A. 2017. The inhibitory impacts of Lactobacillus rhamnosus GG-derived extracellular vesicles on the growth of hepatic cancer cells. Microb. Pathog. 110, 1–6.

    Article  CAS  PubMed  Google Scholar 

  • Benson, A.B., Venook, A.P., Al-Hawary, M.M., Cederquist, L., Chen, Y.J., Ciombor, K.K., Cohen, S., Cooper, H.S., Deming, D., Engstrom, P.F., et al. 2018. Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 16, 852–871.

    Article  PubMed  Google Scholar 

  • Bhattacharya, B., Low, S.H., Soh, C., Kamal Mustapa, N., Beloueche-Babari, M., Koh, K.X., Loh, J., and Soong, R. 2014. Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype. Br. J. Pharmacol. 171, 3255–3267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown, L., Wolf, J.M., Prados-Rosales, R., and Casadevall, A. 2015. Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi. Nat. Rev. Microbiol. 13, 620–630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cairns, R.A., Harris, I.S., and Mak, T.W. 2011. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95.

    Article  CAS  PubMed  Google Scholar 

  • Cao, Z. and Liu, J. 2020. Bacteria and bacterial derivatives as drug carriers for cancer therapy. J. Control Release 326, 396–407.

    Article  CAS  PubMed  Google Scholar 

  • Chen, Z., Lu, W., Garcia-Prieto, C., and Huang, P. 2007. The Warburg effect and its cancer therapeutic implications. J. Bioenerg. Biomembr. 39, 267–274.

    Article  CAS  PubMed  Google Scholar 

  • Chen, Y., Xu, Y., Zhong, H., Yuan, H., Liang, F., Liu, J., and Tang, W. 2021. Extracellular vesicles in Inter-Kingdom communication in gastrointestinal cancer. Am. J. Cancer Res. 11, 1087–1103.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Choi, J., Kim, Y.K., and Han, P.L. 2019. Extracellular vesicles derived from Lactobacillus plantarum increase BDNF expression in cultured hippocampal neurons and produce antidepressant-like effects in mice. Exp. Neurobiol. 28, 158–171.

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi, J.H., Moon, C.M., Shin, T.S., Kim, E.K., McDowell, A., Jo, M.K., Joo, Y.H., Kim, S.E., Jung, H.K., Shim, K.N., et al. 2020. Lactobacillus paracasei-derived extracellular vesicles attenuate the intestinal inflammatory response by augmenting the endoplasmic reticulum stress pathway. Exp. Mol. Med. 52, 423–437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Contractor, T. and Harris, C.R. 2012. p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res. 72, 560–567.

    Article  CAS  PubMed  Google Scholar 

  • Floter, J., Kaymak, I., and Schulze, A. 2017. Regulation of metabolic activity by p53. Metabolites 7, 21.

    Article  PubMed Central  CAS  Google Scholar 

  • Ganapathy-Kanniappan, S. and Geschwind, J.F. 2013. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol. Cancer 12, 152.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hammond, W.A., Swaika, A., and Mody, K. 2016. Pharmacologic resistance in colorectal cancer: a review. Ther. Adv. Med. Oncol. 8, 57–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanahan, D. and Weinberg, R.A. 2011. Hallmarks of cancer: the next generation. Cell 144, 646–674.

    Article  CAS  PubMed  Google Scholar 

  • Hulse, M., Caruso, L.B., Madzo, J., Tan, Y., Johnson, S., and Tempera, I. 2018. Poly(ADP-ribose) polymerase 1 is necessary for coactivating hypoxia-inducible factor-1-dependent gene expression by Epstein-Barr virus latent membrane protein 1. PLoS Pathog. 14, e1007394.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kang, E.A., Choi, H.I., Hong, S.W., Kang, S., Jegal, H.Y., Choi, E.W., Park, B.S., and Kim, J.S. 2020. Extracellular vesicles derived from kefir grain Lactobacillus ameliorate intestinal inflammation via regulation of proinflammatory pathway and tight junction integrity. Biomedicines 8, 522.

    Article  CAS  PubMed Central  Google Scholar 

  • Kim, H.J., An, J., and Ha, E.M. 2022. Lactobacillus plantarum-derived metabolites sensitize the tumor-suppressive effects of butyrate by regulating the functional expression of SMCT1 in 5-FU-resistant colorectal cancer cells. J. Microbiol. 60, 100–117.

    Article  CAS  PubMed  Google Scholar 

  • Kim, M.H., Choi, S.J., Choi, H.I., Choi, J.P., Park, H.K., Kim, E.K., Kim, M.J., Moon, B.S., Min, T.K., Rho, M., et al. 2018a. Lactobacillus plantarum-derived extracellular vesicles protect atopic dermatitis induced by Staphylococcus aureus-derived extracellular vesicles. Allergy Asthma Immunol. Res. 10, 516–532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, J.W. and Dang, C.V. 2005. Multifaceted roles of glycolytic enzymes. Trends Biochem. Sci. 30, 142–150.

    Article  CAS  PubMed  Google Scholar 

  • Kim, M.J., Kim, K.P., Choi, E., Yim, J.H., Choi, C., Yun, H.S., Ahn, H.Y., Oh, J.Y., and Cho, Y. 2021. Effects of Lactobacillus plantarum CJLP55 on clinical improvement, skin condition and urine bacterial extracellular vesicles in patients with acne vulgaris: a randomized, double-blind, placebo-controlled study. Nutrients 13, 1368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, H., Kim, H.S., Park, W.J., and Chung, D.K. 2015a. Inhibitory effect of Lactobacillus plantarum extracts on HT-29 colon cancer cell apoptosis induced by Staphylococcus aureus and its alphatoxin. J. Microbiol. Biotechnol. 25, 1849–1855.

    Article  CAS  PubMed  Google Scholar 

  • Kim, S.Y., Kwon, S.K., Lee, S.Y., and Baek, K.H. 2018b. Ubiquitin-specific peptidase 5 and ovarian tumor deubiquitinase 6A are differentially expressed in p53+/+ and p53−/− HCT116 cells. Int. J. Oncol. 52, 1705–1714.

    CAS  PubMed  Google Scholar 

  • Kim, W., Lee, E.J., Bae, I.H., Myoung, K., Kim, S.T., Park, P.J., Lee, K.H., Pham, A.V.Q., Ko, J., Oh, S.H., et al. 2020. Lactobacillus plantarum-derived extracellular vesicles induce anti-inflammatory M2 macrophage polarization in vitro. J. Extracell. Vesicles 9, 1793514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, J.H., Lee, J., Park, J., and Gho, Y.S. 2015b. Gram-negative and Gram-positive bacterial extracellular vesicles. Semin. Cell Dev. Biol. 40, 97–104.

    Article  CAS  PubMed  Google Scholar 

  • Kim, J.W., Tchernyshyov, I., Semenza, G.L., and Dang, C.V. 2006. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 3, 177–185.

    Article  PubMed  CAS  Google Scholar 

  • Lee, B.H., Wu, S.C., Shen, T.L., Hsu, Y.Y., Chen, C.H., and Hsu, W.H. 2021. The applications of Lactobacillus plantarum-derived extracellular vesicles as a novel natural antibacterial agent for improving quality and safety in tuna fish. Food Chem. 340, 128104.

    Article  CAS  PubMed  Google Scholar 

  • Li, W., Deng, X., and Chen, T. 2021. Exploring the modulatory effects of gut microbiota in anti-cancer therapy. Front. Oncol. 11, 644454.

    Article  PubMed  PubMed Central  Google Scholar 

  • Li, M., Lee, K., Hsu, M., Nau, G., Mylonakis, E., and Ramratnam, B. 2017. Lactobacillus-derived extracellular vesicles enhance host immune responses against vancomycin-resistant enterococci. BMC Microbiol. 17, 66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liang, Y., Hou, L., Li, L., Li, L., Zhu, L., Wang, Y., Huang, X., Hou, Y., Zhu, D., Zou, H., et al. 2020. Dichloroacetate restores colorectal cancer chemosensitivity through the p53/miR-149-3p/PDK2-mediated glucose metabolic pathway. Oncogene 39, 469–485.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Y., Defourny, K.A.Y., Smid, E.J., and Abee, T. 2018. Gram-positive bacterial extracellular vesicles and their impact on health and disease. Front. Microbiol. 9, 1502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, J., Zhang, C., Hu, W., and Feng, Z. 2019. Tumor suppressor p53 and metabolism. J. Mol. Cell. Biol. 11, 284–292.

    Article  CAS  PubMed  Google Scholar 

  • Longley, D.B., Harkin, D.P., and Johnston, P.G. 2003. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330–338.

    Article  CAS  PubMed  Google Scholar 

  • Longley, D.B. and Johnston, P.G. 2005. Molecular mechanisms of drug resistance. J. Pathol. 205, 275–292.

    Article  CAS  PubMed  Google Scholar 

  • Marcus, M.E. and Leonard, J.N. 2013. FedExosomes: engineering therapeutic biological nanoparticles that truly deliver. Pharmaceuticals 6, 659–680.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinez-Outschoorn, U.E., Lin, Z., Ko, Y.H., Goldberg, A.F., Flomenberg, N., Wang, C., Pavlides, S., Pestell, R.G., Howell, A., Sotgia, F., et al. 2011. Understanding the metabolic basis of drug resistance: therapeutic induction of the Warburg effect kills cancer cells. Cell Cycle 10, 2521–2528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miller, K.D., Siegel, R.L., Lin, C.C., Mariotto, A.B., Kramer, J.L., Rowland, J.H., Stein, K.D., Alteri, R., and Jemal, A. 2016. Cancer treatment and survivorship statistics, 2016. CA Cancer J. Clin. 66, 271–289.

    Article  PubMed  Google Scholar 

  • Pavlova, N.N., Zhu, J., and Thompson, C.B. 2022. The hallmarks of cancer metabolism: still emerging. Cell Metab. 34, 355–377.

    Article  CAS  PubMed  Google Scholar 

  • Popov, K.M., Kedishvili, N.Y., Zhao, Y., Gudi, R., and Harris, R.A. 1994. Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase. J. Biol. Chem. 269, 29720–29724.

    Article  CAS  PubMed  Google Scholar 

  • Sancho, P., Barneda, D., and Heeschen, C. 2016. Hallmarks of cancer stem cell metabolism. Br. J. Cancer 114, 1305–1312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen, Y.C., Ou, D.L., Hsu, C., Lin, K.L., Chang, C.Y., Lin, C.Y., Liu, S.H., and Cheng, A.L. 2013. Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes sorafenib resistance of hepatocellular carcinoma. Br. J. Cancer 108, 72–81.

    Article  CAS  PubMed  Google Scholar 

  • Shi, Y., Meng, L., Zhang, C., Zhang, F., and Fang, Y. 2022. Extracellular vesicles of Lacticaseibacillus paracasei PC-H1 induce colorectal cancer cells apoptosis via PDK1/AKT/Bcl-2 signaling pathway. Microbiol. Res. 259, 126955.

    Article  PubMed  Google Scholar 

  • Shin, Y.M., Han, H.S., Lim, S.W., Kim, B.C., Cheoi, K.S., Eum, Y.O., Kim, S.T., and Lee, K.H. 2005. Combination chemotherapy of oxaliplatin, 5-fluorouracil and low dose leucovorin in patients with advanced colorectal cancer. Cancer Res. Treat. 37, 284–289.

    Article  PubMed  PubMed Central  Google Scholar 

  • Stacpoole, P.W. 2017. Therapeutic targeting of the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis in cancer. J. Natl. Cancer Inst. 109, djx071.

    Article  CAS  Google Scholar 

  • Sun, W., Zhou, S., Chang, S.S., McFate, T., Verma, A., and Califano, J.A. 2009. Mitochondrial mutations contribute to HIF1a accumulation via increased reactive oxygen species and up-regulated pyruvate dehydrogenease kinase 2 in head and neck squamous cell carcinoma. Clin. Cancer Res. 15, 476–484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun, H., Zhu, A., Zhou, X., and Wang, F. 2017. Suppression of pyruvate dehydrogenase kinase-2 re-sensitizes paclitaxel-resistant human lung cancer cells to paclitaxel. Oncotarget. 8, 52642–52650.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., and Bray, F. 2021. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249.

    Article  PubMed  Google Scholar 

  • Sutendra, G., Dromparis, P., Kinnaird, A., Stenson, T.H., Haromy, A., Parker, J.M.R., McMurtry, M.S., and Michelakis, E.D. 2013. Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer. Oncogene 32, 1638–1650.

    Article  CAS  PubMed  Google Scholar 

  • Sutendra, G. and Michelakis, E.D. 2013. Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology. Front. Oncol. 3, 38.

    Article  PubMed  PubMed Central  Google Scholar 

  • Théry, C., Witwer, K.W., Aikawa, E., Alcaraz, M.J., Anderson, J.D., Andriantsitohaina, R., Antoniou, A., Arab, T., Archer, F., Atkin-Smith, G.K., et al. 2018. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tuerhong, A., Xu, J., Shi, S., Tan, Z., Meng, Q., Hua, J., Liu, J., Zhang, B., Wang, W., Yu, X., et al. 2021. Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles’ heel of pancreatic ductal adenocarcinoma. Cell. Mol. Life Sci. 78, 5505–5526.

    Article  CAS  PubMed  Google Scholar 

  • Vander Heiden, M.G., Cantley, L.C., and Thompson, C.B. 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Veenstra, C.M. and Krauss, J.C. 2018. Emerging systemic therapies for colorectal cancer. Clin. Colon Rectal Surg. 31, 179–191.

    Article  PubMed  PubMed Central  Google Scholar 

  • Warburg, O. 1956. On the origin of cancer cells. Science 123, 309–314.

    Article  CAS  PubMed  Google Scholar 

  • Xu, R.H., Pelicano, H., Zhou, Y., Carew, J.S., Feng, L., Bhalla, K.N., Keating, M.J., and Huang, P. 2005. Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 65, 613–621.

    Article  CAS  PubMed  Google Scholar 

  • Xuan, Y., Hur, H., Ham, I.H., Yun, J., Lee, J.Y., Shim, W., Kim, Y.B., Lee, G., Han, S.U., and Cho, Y.K. 2014. Dichloroacetate attenuates hypoxia-induced resistance to 5-fluorouracil in gastric cancer through the regulation of glucose metabolism. Exp. Cell Res. 321, 219–230.

    Article  CAS  PubMed  Google Scholar 

  • Yue, Y., Yang, B., Lu, J., Zhang, S., Liu, L., Nassar, K., Xu, X., Pang, X., and Lv, J. 2020a. Metabolite secretions of Lactobacillus plantarum YYC-3 may inhibit colon cancer cell metastasis by suppressing the VEGF-MMP2/9 signaling pathway. Microb. Cell Fact. 19, 213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yue, Y., Ye, K., Lu, J., Wang, X., Zhang, S., Liu, L., Yang, B., Nassar, K., Xu, X., Pang, X., et al. 2020b. Probiotic strain Lactobacillus plantarum YYC-3 prevents colon cancer in mice by regulating the tumour microenvironment. Biomed. Pharmacother. 127, 110159.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, N., Yin, Y., Xu, S.J., and Chen, W.S. 2008. 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules 13, 1551–1569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao, Y., Butler, E.B., and Tan, M. 2013. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 4, e532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou, Y., Tozzi, F., Chen, J., Fan, F., Xia, L., Wang, J., Gao, G., Zhang, A., Xia, X., Brasher, H., et al. 2012. Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 72, 304–314.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowlegements

None.

Author information

Authors and Affiliations

  1. Gyeongbuk Techno Park, Medical Convergence Textile Center, Gyeongsan, 38408, Republic of Korea

    JaeJin An

  2. College of Pharmacy, Daegu Catholic University, Gyeongsan, 38430, Republic of Korea

    Eun-Mi Ha

Authors
  1. JaeJin An
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eun-Mi Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eun-Mi Ha.

Additional information

Conflict of Interest

The authors have no conflict of interest to report.

Supplementary Materials and Methods

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

An, J., Ha, EM. Extracellular vesicles derived from Lactobacillus plantarum restore chemosensitivity through the PDK2-mediated glucose metabolic pathway in 5-FU-resistant colorectal cancer cells. J Microbiol. 60, 735–745 (2022). https://doi.org/10.1007/s12275-022-2201-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords

Search

Navigation