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

• Published in: Molecules (Basel, Switzerland) Vol. 22; no. 6; p. 1024
• Main Authors: Hernández-Padilla, Laura, Vázquez-Rivera, Dolores, Sánchez-Briones, Luis A, Díaz-Pérez, Alma L, Moreno-Rodríguez, José, Moreno-Eutimio, Mario A, Meza-Carmen, Victor, Cruz, Homero Reyes-De la, Campos-García, Jesús
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 20-06-2017; MDPI
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Akt–S6k signaling; Antiproliferatives; antitumoral activity; Apoptosis; Apoptosis - drug effects; biomolecule; Caspase; Caspase 3 - metabolism; Caspase 9 - metabolism; Caspase-9; Cell Cycle; Cell death; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cell Survival; Chromatography, High Pressure Liquid; cyclodipeptides; Dipeptides - isolation & purification; Dipeptides - metabolism; Dipeptides - pharmacology; HeLa; HeLa Cells; Humans; Inhibition; Kinases; Lethal Dose 50; Membrane potential; Mitochondria; Peptides, Cyclic - chemistry; Peptides, Cyclic - isolation & purification; Peptides, Cyclic - pharmacology; Phosphorylation; Phosphorylation - drug effects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pseudomonas aeruginosa; Pseudomonas aeruginosa - chemistry; Ribosomal Protein S6 Kinases - metabolism; Signal transduction; Signal Transduction - drug effects; TOR protein; HeLa; antitumoral activity; cell proliferation; cyclodipeptides; Akt–S6k signaling; apoptosis; biomolecule
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22061024

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 (LD
of 60-250 µM) and inducing apoptosis with EC
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.