Antiproliferative effect of bacterial cyclodipeptides in the HeLa line of human cervical cancer reveals multiple protein
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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 Laura Hernández‑Padilla1 · Homero Reyes de la Cruz2 · Jesús Campos‑García1
© Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Antiproliferation · Anti-neoplastic drugs · Cervix adenocarcinoma · Cyclodipeptides · Malignancy · Protein kinases
Introduction Cancer is caused by the malfunction of fundamental cellular processes modulating the number of cells, as well as cellular growth, proliferation, survival, and energy metabolism. In this sense, oncogenes and tumor suppressors, such as PI3K, Akt, Ras, Raf, TRK, NF1, LKN1, PTEN, P53, TSC1, and TSC2, have been widely documented in cancer diseases [1]. * Jesús Campos‑García [email protected] 1
Laboratorio de Biotecnología Microbiana, Instituto de Investigaciones Químico‑Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, 58030 Morelia, Michoacán, México
Laboratorio de Transducción de Señal, Instituto de Investigaciones Químico‑Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, México
2
Cervical cancer (CC) is one common type of gynecologic cancer that is responsible for cancer-related death in women worldwide, which occurs due to the infection by certain types of the human papillomavirus (HPV), particularly types 16, 18, 33, and 42 [2, 3]. CC is characterized by poor diagnosis, high recurrence rates, and drug resistance. Consequently, CC patients have a relatively poor prognosis
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