Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 15, Pages -Publisher
MDPI
DOI: 10.3390/ijms22158268
Keywords
hinokitiol; endometrial cancer; apoptosis; reactive oxygen species
Funding
- Ministry of Science and Technology, Taiwan [MOST109-2314-B-038-059, MOST 109-2628-B-038015, MOST 109-2320-B-254-001, MOST 109-2811-B-038-523, MOST 109-2320-B-424-001]
- Shin Kong Wu Ho-Su Memorial Hospital, Taiwan [SKH-TMU-107-05]
- Ministry of Education, Taiwan [MOE-RSC-108RSN0005]
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Hinokitiol exerts anti-proliferative effects on endometrial cancer cells by inhibiting cell cycle mediators, promoting apoptosis, inducing autophagy, and triggering ROS production. These findings suggest potential therapeutic benefits of hinokitiol in endometrial cancer treatment.
Hinokitiol is a natural tropolone derivative that is present in the heartwood of cupressaceous plants, and has been extensively investigated for its anti-inflammatory, antioxidant, and antitumor properties in the context of various diseases. To date, the effects of hinokitiol on endometrial cancer (EC) has not been explored. The purpose of our study was to investigate the anti-proliferative effects of hinokitiol on EC cells. Cell viability was determined with an MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the quantification of apoptosis and reactive oxygen species (ROSs) was performed by using flow cytometry, while protein expression was measured with the Western blotting technique. Hinokitiol significantly suppressed cell proliferation through the inhibition of the expression of cell-cycle mediators, such as cyclin D1 and cyclin-dependent kinase 4 (CDK4), as well as the induction of the tumor suppressor protein p53. In addition, hinokitiol increased the number of apoptotic cells and increased the protein expression of cleaved-poly-ADP-ribose polymerase (PARP) and active cleaved-caspase-3, as well as the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2). Interestingly, except for KLE cells, hinokitiol induced autophagy by promoting the accumulation of the microtubule-associated protein light chain 3B (LC3B) and reducing the sequestosome-1 (p62/SQSTM1) protein level. Furthermore, hinokitiol triggered ROS production and upregulated the phosphorylation of extracellular-signal-regulated kinase (p-ERK1/2) in EC cells. These results demonstrate that hinokitiol has potential anti-proliferative and pro-apoptotic benefits in the treatment of endometrial cancer cell lines (Ishikawa, HEC-1A, and KLE).
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