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Antiproliferative effect of bacterial cyclodipeptides in the HeLa line of human cervical cancer reveals multiple protein kinase targeting, including mTORC1/C2 complex inhibition in a TSC1/2-dependent manner

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Abstract

Cervix adenocarcinoma rendered by human papillomavirus (HPV) integration is an aggressive cancer that occurs by dysregulation of multiple pathways, including oncogenes, proto-oncogenes, and tumor suppressors. The PI3K/Akt/mTOR pathway, which cross-talks with the Ras–ERK pathway, has been associated with cervical cancers (CC), which includes signaling pathways related to carcinoma aggressiveness, metastasis, recurrence, and drug resistance. Since bacterial cyclodipeptides (CDPs) possess cytotoxic properties in HeLa cells with inhibiting Akt/S6k phosphorylation, the mechanism of CDPs cytotoxicity involved was deepened. Results showed that the antiproliferative effect of CDPs occurred by blocking the PI3K/Akt/mTOR pathway, inhibiting the mTORC1/mTORC2 complexes in a TSC1/TSC2-dependent manner. In addition, the CDPs blocked protein kinases from multiple signaling pathways involved in survival, proliferation, invasiveness, apoptosis, autophagy, and energy metabolism, such as PI3K/Akt/mTOR, Ras/Raf/MEK/ERK1/2, PI3K/JNK/PKA, p27Kip1/CDK1/survivin, MAPK, HIF-1, Wnt/β-catenin, HSP27, EMT, CSCs, and receptors, such as EGF/ErbB2/HGF/Met. Thus, the antiproliferative effect of the CDPs made it possible to identify the crosstalk of the signaling pathways involved in HeLa cell malignancy and to suggest that bacterial CDPs may be considered as a potential anti-neoplastic drug in human cervical adenocarcinoma therapy.

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Acknowledgements

This study was funded by the Consejo Nacional de Ciencia y Tecnología (CONACYT) of México (Grant Numbers 256119 and 222405), the Marcos Moshinsky Foundation, and Universidad Michoacana de San Nicolás de Hidalgo/C.I.C.2.14 Grants. L.H.-P. received a scholarship from CONACYT. We thank Alejandra Ochoa for HeLa cell line donation.

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Authors and Affiliations

  1. Laboratorio de Biotecnología Microbiana, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, 58030, Morelia, Michoacán, México

    Laura Hernández-Padilla & Jesús Campos-García

  2. Laboratorio de Transducción de Señal, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, México

    Homero Reyes de la Cruz

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  1. Laura Hernández-Padilla
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  2. Homero Reyes de la Cruz
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Conception and design: JC-G, LH-P. Analysis and interpretation of data: LH-P, JC-G. Writing, review, and/or revision of the manuscript: JC-G, LH-P, HR-C. Administrative, technical, or material support: JC-G, HR-C.

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Correspondence to Jesús Campos-García.

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Hernández-Padilla, L., Reyes de la Cruz, H. & Campos-García, J. Antiproliferative effect of bacterial cyclodipeptides in the HeLa line of human cervical cancer reveals multiple protein kinase targeting, including mTORC1/C2 complex inhibition in a TSC1/2-dependent manner. Apoptosis 25, 632–647 (2020). https://doi.org/10.1007/s10495-020-01619-z

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