1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione induces G1 cell cycle arrest and autophagy in HeLa cervical cancer cells
Journal
International Journal of Molecular Sciences
Journal Volume
17
Journal Issue
8
Date Issued
2016
Author(s)
Abstract
The natural agent, 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB), has been reported to have growth inhibitory effects on several human cancer cells. However, the role of HMDB in cervical cancer remains unclear. Herein, we found that HMDB dose-and time-dependently inhibited growth of HeLa cervical cancer cells, accompanied with G1 cell cycle arrest. HMDB decreased protein expression of cyclins D1/D3/E and cyclin-dependent kinases (CDKs) 2/4/6 and reciprocally increased mRNA and protein levels of CDK inhibitors (p15, p16, p21, and p27), thereby leading to the accumulation of hypophosphorylated retinoblastoma (Rb) protein. HMDB also triggered the accumulation of acidic vesicles and formation of microtubule-associated protein-light chain 3 (LC3), followed by increased expression of LC3 and Beclin-1 and decreased expression of p62, suggesting that HMDB triggered autophagy in HeLa cells. Meanwhile, suppression of the expression of survivin and Bcl-2 implied that HMDB-induced autophagy is tightly linked to apoptosis. Exploring the action mechanism, HMDB induced autophagy via the modulation of AMP-activated protein kinase (AMPK) and mTOR signaling pathway rather than the class III phosphatidylinositol 3-kinase pathway. These results suggest that HMDB inhibits HeLa cell growth by eliciting a G1 arrest through modulation of G1 cell cycle regulators and by concomitantly inducing autophagy through the mediation of AMPK-mTOR and Akt-mTOR pathways, and may be a promising antitumor agent against cervical cancer. ? 2016 by the authors; licensee MDPI, Basel, Switzerland.
Subjects
1-(2-hydroxy-5-methylphenyl)-3-phenyl-1; 3-propanedione; Autophagy; Beclin-1; G1 arrest; Light chain 3 (LC3); P62
SDGs
Other Subjects
1 (2 hydroxy 5 methylphenyl) 3 phenyl 1,3 propanedione; antineoplastic agent; beclin 1; cyclin D1; cyclin D3; cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin dependent kinase 6; cyclin dependent kinase inhibitor 1A; cyclin dependent kinase inhibitor 1B; cyclin dependent kinase inhibitor 2A; cyclin dependent kinase inhibitor 2B; cyclin E; hydroxymethylglutaryl coenzyme A reductase kinase; mammalian target of rapamycin; phosphatidylinositol 3 kinase; protein bcl 2; protein kinase B; protein p62; retinoblastoma protein; unclassified drug; 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione; beclin 1; BECN1 protein, human; cell cycle protein; hydroxymethylglutaryl coenzyme A reductase kinase; ketone; light chain 3, human; microtubule associated protein; propane; protein kinase B; target of rapamycin kinase; apoptosis; Article; autophagy; cancer growth; cancer inhibition; cell cycle assay; controlled study; down regulation; G1 phase cell cycle checkpoint; gene expression regulation; high performance liquid chromatography; human; human cell; immunofluorescence; microtubule assembly; MTT assay; protein expression; protein phosphorylation; real time polymerase chain reaction; TUNEL assay; uterine cervix cancer; Western blotting; analogs and derivatives; autophagy; biological model; cell proliferation; cell vacuole; chemistry; drug effects; female; G1 phase cell cycle checkpoint; HeLa cell line; lysosome; metabolism; pathology; signal transduction; uterine cervix tumor; AMP-Activated Protein Kinases; Apoptosis; Autophagy; Beclin-1; Cell Cycle Proteins; Cell Proliferation; Female; G1 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; Ketones; Lysosomes; Microtubule-Associated Proteins; Models, Biological; Propane; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Uterine Cervical Neoplasms; Vacuoles
Type
journal article
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