The (+)-Brevipolide H Displays Anticancer Activity against Human Castration-Resistant Prostate Cancer: The Role of Oxidative Stress and Akt/mTOR/p70S6K-Dependent Pathways in G1 Checkpoint Arrest and Apoptosis
Open Access
- 25 June 2020
- Vol. 25 (12), 2929
- https://doi.org/10.3390/molecules25122929
Abstract
Because conventional chemotherapy is not sufficiently effective against prostate cancer, various examinations have been performed to identify anticancer activity of naturally occurring components and their mechanisms of action. The (+)-brevipolide H, an α-pyrone-based natural compound, induced potent and long-term anticancer effects in human castration-resistant prostate cancer (CRPC) PC-3 cells. Flow cytofluorometric analysis with propidium iodide staining showed (+)-brevipolide H-induced G1 arrest of cell cycle and subsequent apoptosis through induction of caspase cascades. Since Akt/mTOR pathway has been well substantiated in participating in cell cycle progression in G1 phase, its signaling and downstream regulators were examined. Consequently, (+)-brevipolide H inhibited the signaling pathway of Akt/mTOR/p70S6K. The c-Myc inhibition and downregulation of G1 phase cyclins were also attributed to (+)-brevipolide H action. Overexpression of myristoylated Akt significantly rescued mTOR/p70S6K and downstream signaling under (+)-brevipolide H treatment. ROS and Ca2+, two key mediators in regulating intracellular signaling, were determined, showing that (+)-brevipolide H interactively induced ROS production and an increase of intracellular Ca2+ levels. The (+)-Brevipolide H also induced the downregulation of anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xL) and loss of mitochondrial membrane potential, indicating the contribution of mitochondrial dysfunction to apoptosis. In conclusion, the data suggest that (+)-brevipolide H displays anticancer activity through crosstalk between ROS production and intracellular Ca2+ mobilization. In addition, suppression of Akt/mTOR/p70S6K pathway associated with downregulation of G1 phase cyclins contributes to (+)-brevipolide H-mediated anticancer activity, which ultimately causes mitochondrial dysfunction and cell apoptosis. The data also support the biological significance and, possibly, clinically important development of natural product-based anticancer approaches.Funding Information
- Ministry of Science and Technology, Taiwan (MOST 107-2320-B-002-018-MY3 and MOST 106-2320-B-002 -005 -MY3)
This publication has 60 references indexed in Scilit:
- PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signalingMolecular Cancer, 2013
- Remodeling of calcium signaling in tumor progressionJournal of Biomedical Science, 2013
- Absolute Configuration and Conformational Analysis of Brevipolides, Bioactive 5,6-Dihydro-α-pyrones from Hyptis brevipesJournal of Natural Products, 2013
- Mitochondrial Regulation of Cell Cycle and ProliferationAntioxidants and Redox Signaling, 2012
- Bioactive 5,6-Dihydro-α-pyrone Derivatives from Hyptis brevipesJournal of Natural Products, 2009
- Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosisOncogene, 2008
- Phosphoinositide 3-Kinase Activation in Late G1 Is Required for c-Myc Stabilization and S Phase EntryMolecular and Cellular Biology, 2006
- Three new compounds from the plant Lippia alva as inhibitors of chemokine receptor 5 (CCR5)Bioorganic & Medicinal Chemistry Letters, 2004
- Expression of the Ca2+-selective cation channel TRPV6 in human prostate cancer: a novel prognostic marker for tumor progressionOncogene, 2003
- Superoxide activates mitochondrial uncoupling proteinsNature, 2002