The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase
Abstract Background Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, posing a serious public health challenge that necessitates the development of new therapeutics, therapies, and prevention methods. Among the various therapeutic approaches, interventions involving lactic acid...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Microbial Cell Factories |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12934-024-02345-w |
| _version_ | 1797258979521331200 |
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| author | Rafał Jastrząb Rafał Tomecki Aneta Jurkiewicz Damian Graczyk Agnieszka K. Szczepankowska Jennifer Mytych Damian Wolman Pawel Siedlecki |
| author_facet | Rafał Jastrząb Rafał Tomecki Aneta Jurkiewicz Damian Graczyk Agnieszka K. Szczepankowska Jennifer Mytych Damian Wolman Pawel Siedlecki |
| author_sort | Rafał Jastrząb |
| collection | DOAJ |
| description | Abstract Background Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, posing a serious public health challenge that necessitates the development of new therapeutics, therapies, and prevention methods. Among the various therapeutic approaches, interventions involving lactic acid bacteria (LAB) as probiotics and postbiotics have emerged as promising candidates for treating and preventing CRC. While human-isolated LAB strains are considered highly favorable, those sourced from environmental reservoirs such as dairy and fermented foods are also being recognized as potential sources for future therapeutics. Results In this study, we present a novel and therapeutically promising strain, Lactococcus lactis ssp. lactis Lc4, isolated from dairy sources. Lc4 demonstrated the ability to release the cytostatic agent - arginine deiminase (ADI) - into the post-cultivation supernatant when cultured under conditions mimicking the human gut environment. Released arginine deiminase was able to significantly reduce the growth of HT-29 and HCT116 cells due to the depletion of arginine, which led to decreased levels of c-Myc, reduced phosphorylation of p70-S6 kinase, and cell cycle arrest. The ADI release and cytostatic properties were strain-dependent, as was evident from comparison to other L. lactis ssp. lactis strains. Conclusion For the first time, we unveil the anti-proliferative properties of the L. lactis cell-free supernatant (CFS), which are independent of bacteriocins or other small molecules. We demonstrate that ADI, derived from a dairy-Generally Recognized As Safe (GRAS) strain of L. lactis, exhibits anti-proliferative activity on cell lines with different levels of argininosuccinate synthetase 1 (ASS1) expression. A unique feature of the Lc4 strain is also its capability to release ADI into the extracellular space. Taken together, we showcase L. lactis ADI and the Lc4 strain as promising, potential therapeutic agents with broad applicability. |
| first_indexed | 2024-04-24T23:02:08Z |
| format | Article |
| id | doaj.art-f921edc8c32a40359c88a84053354c17 |
| institution | Directory Open Access Journal |
| issn | 1475-2859 |
| language | English |
| last_indexed | 2024-04-24T23:02:08Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Microbial Cell Factories |
| spelling | doaj.art-f921edc8c32a40359c88a84053354c172024-03-17T12:42:53ZengBMCMicrobial Cell Factories1475-28592024-03-0123112010.1186/s12934-024-02345-wThe strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminaseRafał Jastrząb0Rafał Tomecki1Aneta Jurkiewicz2Damian Graczyk3Agnieszka K. Szczepankowska4Jennifer Mytych5Damian Wolman6Pawel Siedlecki7Institute of Biochemistry and Biophysics, Polish Academy of SciencesInstitute of Biochemistry and Biophysics, Polish Academy of SciencesInstitute of Biochemistry and Biophysics, Polish Academy of SciencesInstitute of Biochemistry and Biophysics, Polish Academy of SciencesInstitute of Biochemistry and Biophysics, Polish Academy of SciencesOlimp LaboratoriesOlimp LaboratoriesInstitute of Biochemistry and Biophysics, Polish Academy of SciencesAbstract Background Colorectal cancer (CRC) is one of the most commonly diagnosed cancers, posing a serious public health challenge that necessitates the development of new therapeutics, therapies, and prevention methods. Among the various therapeutic approaches, interventions involving lactic acid bacteria (LAB) as probiotics and postbiotics have emerged as promising candidates for treating and preventing CRC. While human-isolated LAB strains are considered highly favorable, those sourced from environmental reservoirs such as dairy and fermented foods are also being recognized as potential sources for future therapeutics. Results In this study, we present a novel and therapeutically promising strain, Lactococcus lactis ssp. lactis Lc4, isolated from dairy sources. Lc4 demonstrated the ability to release the cytostatic agent - arginine deiminase (ADI) - into the post-cultivation supernatant when cultured under conditions mimicking the human gut environment. Released arginine deiminase was able to significantly reduce the growth of HT-29 and HCT116 cells due to the depletion of arginine, which led to decreased levels of c-Myc, reduced phosphorylation of p70-S6 kinase, and cell cycle arrest. The ADI release and cytostatic properties were strain-dependent, as was evident from comparison to other L. lactis ssp. lactis strains. Conclusion For the first time, we unveil the anti-proliferative properties of the L. lactis cell-free supernatant (CFS), which are independent of bacteriocins or other small molecules. We demonstrate that ADI, derived from a dairy-Generally Recognized As Safe (GRAS) strain of L. lactis, exhibits anti-proliferative activity on cell lines with different levels of argininosuccinate synthetase 1 (ASS1) expression. A unique feature of the Lc4 strain is also its capability to release ADI into the extracellular space. Taken together, we showcase L. lactis ADI and the Lc4 strain as promising, potential therapeutic agents with broad applicability.https://doi.org/10.1186/s12934-024-02345-wProbioticsPostbioticsCell-free supernatantAnti-cancerCytostaticArginine deiminase |
| spellingShingle | Rafał Jastrząb Rafał Tomecki Aneta Jurkiewicz Damian Graczyk Agnieszka K. Szczepankowska Jennifer Mytych Damian Wolman Pawel Siedlecki The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase Microbial Cell Factories Probiotics Postbiotics Cell-free supernatant Anti-cancer Cytostatic Arginine deiminase |
| title | The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase |
| title_full | The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase |
| title_fullStr | The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase |
| title_full_unstemmed | The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase |
| title_short | The strain-dependent cytostatic activity of Lactococcus lactis on CRC cell lines is mediated through the release of arginine deiminase |
| title_sort | strain dependent cytostatic activity of lactococcus lactis on crc cell lines is mediated through the release of arginine deiminase |
| topic | Probiotics Postbiotics Cell-free supernatant Anti-cancer Cytostatic Arginine deiminase |
| url | https://doi.org/10.1186/s12934-024-02345-w |
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