期刊
MOLECULES
卷 22, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/molecules22061024
关键词
biomolecule; cyclodipeptides; antitumoral activity; cell proliferation; apoptosis; Akt-S6k signaling; HeLa
资金
- Consejo Nacional de Ciencia y Tecnologia (CONACYT) of Mexico [256119, 167071, 222405]
- Marcos Moshinsky Foundation
- Universidad Michoacana de San Nicolas de Hidalgo [C.I.C.2.14]
- CONACYT
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 mu M) and inducing apoptosis with EC50 between 0.6 and 3.0 mu M. Moreover, PAO1-CDPs showed a higher proapoptotic activity (similar to 10(3)-10(5) 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.
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