1-(2-Hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione Induces G1 Cell Cycle Arrest and Autophagy in HeLa Cervical Cancer Cells.

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.

• Authors: Jie-Heng Tsai, Li-Sung Hsu, Hsiu-Chen Huang, Chih-Li Lin, Min-Hsiung Pan, Hui-Mei Hong, Wei-Jen Chen
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 17 Issue 8 (Aug 05 2016) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 27527160 (Publication Type: Journal Article)

Chemical References

• 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione
• BECN1 protein, human
• Beclin-1
• Cell Cycle Proteins
• Ketones
• MAP1LC3A protein, human
• Microtubule-Associated Proteins
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases
• Propane

Topics

• AMP-Activated Protein Kinases (metabolism)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Beclin-1 (metabolism)
• Cell Cycle Proteins (metabolism)
• Cell Proliferation (drug effects)
• Female
• G1 Phase Cell Cycle Checkpoints (drug effects)
• HeLa Cells
• Humans
• Ketones (chemistry, pharmacology)
• Lysosomes (drug effects, metabolism)
• Microtubule-Associated Proteins (metabolism)
• Models, Biological
• Propane (analogs & derivatives, chemistry, pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Uterine Cervical Neoplasms (pathology)
• Vacuoles (drug effects, metabolism)