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Molecules 2017, 22(6), 1024; doi:10.3390/molecules22061024

The Antiproliferative Effect of Cyclodipeptides from Pseudomonas aeruginosa PAO1 on HeLa Cells Involves Inhibition of Phosphorylation of Akt and S6k Kinases

1
Laboratorio de Biotecnología Microbiana, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, 58030 Morelia, Michoacán, Mexico
2
División de Investigación, Hospital Juárez de México, 07760 Ciudad de México, Mexico
3
Laboratorio de Control Traduccional, Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, 58030 Morelia, Michoacán, Mexico. delacruz@umich.mx
*
Author to whom correspondence should be addressed.
Received: 29 May 2017 / Revised: 14 June 2017 / Accepted: 16 June 2017 / Published: 20 June 2017
(This article belongs to the Special Issue Peptide-Based Drugs and Drug Delivery Systems)
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Abstract

Pseudomonas aeruginosa PAO1, a potential pathogen of plants and animals, produces the cyclodipeptides cyclo(l-Pro-l-Tyr), cyclo(l-Pro-l-Phe), and cyclo(l-Pro-l-Val) (PAO1-CDPs), whose effects have been implicated in inhibition of human tumor cell line proliferation. Our purpose was to investigate in depth in the mechanisms of HeLa cell proliferation inhibition by the PAO1-CDPs. The results indicate that PAO1-CDPs, both purified individually and in mixtures, inhibited HeLa cell proliferation by arresting the cell cycle at the G0–G1 transition. The crude PAO1-CDPs mixture promoted cell death in HeLa cells in a dose-dependent manner, showing efficacy similar to that of isolated PAO1-CDPs (LD50 of 60–250 µM) and inducing apoptosis with EC50 between 0.6 and 3.0 µM. Moreover, PAO1-CDPs showed a higher proapoptotic activity (~103–105 fold) than their synthetic analogs did. Subsequently, the PAO1-CDPs affected mitochondrial membrane potential and induced apoptosis by caspase-9-dependent pathway. The mechanism of inhibition of cells proliferation in HeLa cells involves inhibition of phosphorylation of both Akt-S473 and S6k-T389 protein kinases, showing a cyclic behavior of their expression and phosphorylation in a time and concentration-dependent fashion. Taken together our findings indicate that PI3K–Akt–mTOR–S6k signaling pathway blockage is involved in the antiproliferative effect of the PAO1-CDPs. View Full-Text
Keywords: biomolecule; cyclodipeptides; antitumoral activity; cell proliferation; apoptosis; Akt–S6k signaling; HeLa biomolecule; cyclodipeptides; antitumoral activity; cell proliferation; apoptosis; Akt–S6k signaling; HeLa
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Hernández-Padilla, L.; Vázquez-Rivera, D.; Sánchez-Briones, L.A.; Díaz-Pérez, A.L.; Moreno-Rodríguez, J.; Moreno-Eutimio, M.A.; Meza-Carmen, V.; Cruz, H.-D.; Campos-García, J. The Antiproliferative Effect of Cyclodipeptides from Pseudomonas aeruginosa PAO1 on HeLa Cells Involves Inhibition of Phosphorylation of Akt and S6k Kinases. Molecules 2017, 22, 1024.

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