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Tigecycline suppresses colon cancer stem cells and impairs tumor engraftment by targeting SNAI1-regulated epithelial-mesenchymal transition

Acta Pharmacologica Sinica volume 47, pages 222–241 (2026)Cite this article

Abstract

Cancer stem cells (CSCs) play a key role in the progression of colorectal cancer (CRC). The high heterogeneity of CSCs has hindered the clinical application of CSC-targeting therapies. Tetracyclines are drugs with therapeutic potentials beyond their antibiotic activity. We previously demonstrated the efficacy of tigecycline, a third-generation tetracycline, against a model of colitis-associated colorectal cancer, primarily focusing on its immunomodulatory role with a preliminary assessment of its impact on stemness. In this study we characterize the effects of tigecycline on colon CSCs in vitro and in a CRC xenograft model, with special attention on the signaling pathways involved and the modulation of the gut microbiota. We generated secondary colonospheres from two colon tumor cell lines HCT116 and CMT93, and evaluated the effect of tigecycline on CSCs properties. We showed that tigecycline (25, 50 μM) effectively reduced colon CD133+CD44+LGR5+ALDH+ subpopulations and their viability, self-renewal and migratory capacity. Moreover, tigecycline treatment hindered epithelial-mesenchymal transition (EMT) process through targeting SNAI1 and β-catenin, resulting in an upregulation of epithelial markers (E-cadherin) and a downregulation of pluripotency and mesenchymal ones (Vimentin, N-cadherin, SOX2, NANOG, MIR155, MIR146). This effect was confirmed in two independent CRC-xenograft murine models in which tigecycline administration led to a reduction in tumor volume. Finally, CRC samples were taken from HCT116 xenograft model mice for analysis of CSCs-related signaling pathways and stools were collected for gut microbiome metagenomic analysis. We found that the antibiotic modulated gut dysbiosis by increasing the abundance of beneficial bacterial species such as Parabacteroides sp., which were involved in metabolic pathways that hindered SNAI1-Wnt-β-catenin signaling. These results reinforce the new role of tigecycline in the therapy of CRC and demonstrate for the first time the effect of tigecycline on colon CSCs and their malignancies.

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Fig. 1: Effect of tigecycline on EMT-related genes and miRNAs.
Fig. 2: Impact of tigecycline on tumor colonospheres.
Fig. 3: Tigecycline induces apoptosis in colonospheres.
Fig. 4: Colon CSCs population is reduced by tigecycline in secondary colonospheres derived from HCT116 and CMT93 cell lines.
Fig. 5: Tigecycline reduces the levels of pluripotency and EMT-related genes in secondary colonospheres by hindering SNAI1.
Fig. 6: Tumorigenic capacity of HCT116 xenograft after being treated with tigecycline 50 μM ex vivo.
Fig. 7: Effect of oral administration of tigecycline on HCT116 xenograft mice.
Fig. 8: Oral treatment with tigecycline modulates microbiota composition in tumor xenograft mice.
Fig. 9: Impact of tigecycline on microbiota profile in tumor xenograft mice.
Fig. 10: Main metabolic pathways associated with the gut microbial composition control and tigecycline-treated mice.
Fig. 11: Effect of tigecycline on the metagenomic profile.

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Acknowledgements

The manuscript has been funded by the Junta de Andalucia (CTS164) (Spain) and Fondo Europeo de Desarrollo Regional (FEDER), from the European Union, through the CIBER-EHD and the research grants PY20-01157, B-CTS-664-UGR20, P18-RT-4930, predoctoral grant IFI21/00030 to MJRS, postdoctoral grant CD23/00117 to AJRM, postdoctoral grant CD23/00234 to JGG, postdoctoral grant CD23/00089 to AHP, and POSTDOC_21_638 to CGL. This paper was also supported by Instituto de Salud Carlos III (ISCIII) (Spain) through the projects PI19/01058, PI20/01447 and PI22/0163 and cofounded by the European Union and by the Chair “Doctors Galera-Requena in cancer stem cell research” (CMCCTS963 to JAM).

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Author notes

  1. These authors contributed equally: Antonio Jesús Ruiz-Malagón, María Jesús Rodríguez-Sojo

Authors and Affiliations

  1. Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, 18071, Granada, Spain

    Antonio Jesús Ruiz-Malagón, María Jesús Rodríguez-Sojo, María Elena Rodríguez-Cabezas, Alba Rodríguez-Nogales & Julio Gálvez

  2. Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590, Málaga, Spain

    Antonio Jesús Ruiz-Malagón

  3. Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012, Granada, Spain

    María Jesús Rodríguez-Sojo, Jorge García-García, Ailec Ho-Plagaro, Federico García, Teresa Vezza, Eduardo Redondo-Cerezo, Carmen Griñán-Lisón, Juan Antonio Marchal, María Elena Rodríguez-Cabezas, Alba Rodríguez-Nogales & Julio Gálvez

  4. Servicio de Aparato Digestivo. Hospital Universitario Virgen de las Nieves, 18012, Granada, Spain

    Jorge García-García, Ailec Ho-Plagaro, Teresa Vezza & Eduardo Redondo-Cerezo

  5. Servicio Microbiología, Hospital Universitario Clínico San Cecilio, 18100, Granada, Spain

    Federico García

  6. Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFECC), Instituto de Salud Carlos III, 28029, Madrid, Spain

    Federico García

  7. Department of Biochemistry and Molecular Biology 2, Faculty of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071, Granada, Spain

    Carmen Griñán-Lisón

  8. Centre for Genomics and Oncological Research, GENYO, Pfizer/University of Granada/Andalusian Regional Government, 18016, Granada, Spain

    Carmen Griñán-Lisón

  9. Department of Human Anatomy and Embryology, Biopathology and Regenerative Medicine Institute (IBIMER), Center for Biomedical Research (CIBM), University of Granada, 18016, Granada, Spain

    Juan Antonio Marchal

  10. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029, Madrid, Spain

    Julio Gálvez

Authors
  1. Antonio Jesús Ruiz-Malagón
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  2. María Jesús Rodríguez-Sojo
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  3. Jorge García-García
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  4. Ailec Ho-Plagaro
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  5. Federico García
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  6. Teresa Vezza
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  7. Eduardo Redondo-Cerezo
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  8. Carmen Griñán-Lisón
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  9. Juan Antonio Marchal
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  10. María Elena Rodríguez-Cabezas
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  11. Alba Rodríguez-Nogales
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  12. Julio Gálvez
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Contributions

AJRM, MJRS, ARN and JG conceived and designed the study. AJRM, MJRS, TV, AHP and CGL performed experiments. JGG, AJRM, FG, ARN and JGG performed bioinformatic analysis. AJRM, MJRS, MERC, ERC, JAM, ARN and JG analyzed the results and wrote the manuscript with comments from all authors. ARN, MERC and JG supervised the entire project.

Corresponding authors

Correspondence to María Elena Rodríguez-Cabezas, Alba Rodríguez-Nogales or Julio Gálvez.

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Ruiz-Malagón, A.J., Rodríguez-Sojo, M.J., García-García, J. et al. Tigecycline suppresses colon cancer stem cells and impairs tumor engraftment by targeting SNAI1-regulated epithelial-mesenchymal transition. Acta Pharmacol Sin 47, 222–241 (2026). https://doi.org/10.1038/s41401-025-01629-0

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