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Two Recombinant Bacteriocins, Rhamnosin and Lysostaphin, Show Synergistic Anticancer Activity Against Gemcitabine-Resistant Cholangiocarcinoma Cell Lines

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Abstract

Cholangiocarcinoma (CCA), a bile duct cancer with a high mortality rate, has a poor prognosis due to its highly invasive and drug-resistant phenotypes. More effective and selective therapies are urgently needed. Bacteriocins are broad-spectrum antimicrobial peptides/proteins produced by bacterial strains to compete with other bacteria. Recent studies have reported that bacteriocins exhibit anticancer properties against various cancer cell lines with minimal toxicity toward normal cells. In this study, two types of recombinant bacteriocins, rhamnosin from probiotic Lacticaseibacillus rhamnosus and lysostaphin from Staphylococcus simulans, were highly produced in Escherichia coli and subsequently purified via immobilized-Ni2+ affinity chromatography. When their anticancer activity was investigated against CCA cell lines, both rhamnosin and lysostaphin were found capable of inhibiting the growth of CCA cell lines in a dose-dependent fashion but were less toxic toward a normal cholangiocyte cell line. Rhamnosin and lysostaphin as single treatments could suppress the growth of gemcitabine-resistant cell lines to the same extent as or more than they suppressed the parental counterparts. A combination of both bacteriocins more strongly inhibited growth and enhanced cell apoptosis in both parental and gemcitabine-resistant cells partly through the increased expression of the proapoptotic genes BAX, and caspase-3, -8, and -9. In conclusion, this is the first report to demonstrate an anticancer property of rhamnosin and lysostaphin. Using these bacteriocins as single agents or in combination would be effective against drug-resistant CCA.

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Data Availability

The data used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank Thomas Duncan Coyne, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla, Thailand for assistance with the English editing.

Funding

This work was supported by the National Science, Research and Innovation Fund (NSRF) and Prince of Songkla University (Grant No. SCI6505045S) to Sumalee Obchoei. Kankamol Kerdkumthong was supported by a Prince of Songkla University-Ph.D. Scholarship (PSU_PHD2561-001) and Thesis Research Grant from the Graduate School of Prince of Songkla University. Phonprapavee Tantimetta was supported by a Prince of Songkla University-Ph.D. Scholarship (PSU_PHD2565-002). Sutthipong Nanarong, and Kawinnath Songsurin were supported by a Thesis Research Grant from the Graduate School of Prince of Songkla University.

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Authors and Affiliations

  1. Division of Health and Applied Sciences, Biochemistry Graduate Program, Faculty of Science, Prince of Songkla University, Hatyai, 90110, Songkhla, Thailand

    Kankamol Kerdkumthong, Wannarat Chanket, Phanthipha Runsaeng, Sutthipong Nanarong, Kawinnath Songsurin, Phonprapavee Tantimetta, Aratee Aroonkesorn & Sumalee Obchoei

  2. Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand

    Wannarat Chanket

  3. Bacterial Toxin Research Innovation Laboratory, Institute of Molecular Biosciences, Mahidol University, Salaya Campus, Nakornpathom, 73170, Thailand

    Chanan Angsuthanasombat

  4. Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan

    Chanan Angsuthanasombat

  5. Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand

    Chanan Angsuthanasombat

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  1. Kankamol Kerdkumthong
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Contributions

Sumalee Obchoei, Aratee Aroonkesorn and Kankamol Kerdkumthong contributed to the study conception and design. Kankamol Kerdkumthong, Wannarat Chanket, Sutthipong Nanarong and Phonprapavee Tantimetta carried out the experiments and collected that data. Kawinnath Songsurin established the drug-resistant cell lines. Sumalee Obchoei, Aratee Aroonkesorn, Phanthipha Runsaeng, Kankamol Kerdkumthong and Wannarat Chanket performed data analysis. Chanan Angsuthanasombat was the senior supervisor. The first draft of the manuscript was written by Sumalee Obchoei and Kankamol Kerdkumthong and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sumalee Obchoei.

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Kerdkumthong, K., Chanket, W., Runsaeng, P. et al. Two Recombinant Bacteriocins, Rhamnosin and Lysostaphin, Show Synergistic Anticancer Activity Against Gemcitabine-Resistant Cholangiocarcinoma Cell Lines. Probiotics & Antimicro. Prot. 16, 713–725 (2024). https://doi.org/10.1007/s12602-023-10096-0

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