cyclin-d1 and beta-thujaplicin

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).

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Cell Cycle Checkpoints; Cell Line, Tumor; Cyclin D1; Cyclin-Dependent Kinase 4; Endometrial Neoplasms; Female; Humans; Monoterpenes; Poly(ADP-ribose) Polymerases; Reactive Oxygen Species; Tropolone; Tumor Suppressor Protein p53

β-Thujaplicin, a natural monoterpenoid, has been demonstrated to exert health beneficial activities in chronic diseases. However, it has not been studied in regulating estrogen receptor (ER) negative breast cancer. Here, we investigated the effect of β-thujaplicin on inhibiting ER-negative basal-like breast cancer and the underlying mechanism of action using an in vitro and in vivo xenograft animal model. β-Thujaplicin induced G0/G1 phase cell cycle arrest and regulated cell cycle mediators, cyclin D1, cyclin E, and cyclin-dependent kinase 4 (CDK 4), leading to the inhibition of the proliferation of ER-negative basal-like MCF10DCIS.com human breast cancer cells. It also modulated the phosphorylation of protein kinase B (AKT) and glycogen synthase kinase (GSK-3β) and the protein level of β-catenin. In an MCF10DCIS.com xenograft animal model, β-thujaplicin significantly inhibited tumor growth, reduced tumor weight, and regulated the expression of cell cycle proteins, phosphorylation of AKT and GSK-3β, and protein level of β-catenin in the tumor tissues. These results demonstrate that β-thujaplicin can suppress basal-like mammary tumor growth by regulating GSK-3β/β-catenin signaling, suggesting that β-thujaplicin may be a potent chemopreventive agent against the basal-like subtype of breast cancer.

Topics: Animals; beta Catenin; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Chamaecyparis; Cyclin D1; Cyclin-Dependent Kinase 4; Drugs, Chinese Herbal; Female; G1 Phase Cell Cycle Checkpoints; Glycogen Synthase Kinase 3 beta; Humans; Mice, Inbred BALB C; Monoterpenes; Phosphorylation; Signal Transduction; Thuja; Tropolone

β-Thujaplicin, one of the major constituents in Chamaecyparis obtusa, has been demonstrated to exert different health beneficial efficacy, but the role of β-thujaplicin in regulating mammary tumorigenesis has not been investigated. In this study, we found that β-thujaplicin significantly suppressed the proliferation through arresting the cell cycle transition from G1 to S phase as well as inhibited the expression of cell cycle-related proteins, cyclin D1, and cyclin-dependent kinase 4 (CDK4) in MCF-7 and T47D luminal subtype breast cancer cells. In addition, estrogen receptor α (ER-α) was down-regulated by β-thujaplicin via enhanced proteolysis by ubiquitination, which led to cell growth inhibition. These results suggest that β-thujaplicin may be considered as a potent agent regulating the hormone sensitive mammary tumorigenesis.

Topics: Anticarcinogenic Agents; Breast Neoplasms; Carcinogenesis; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase 4; Estrogen Receptor alpha; G1 Phase Cell Cycle Checkpoints; Humans; MCF-7 Cells; Monoterpenes; Proteolysis; Resting Phase, Cell Cycle; Signal Transduction; Tropolone