The Phosphatidyl Inositol 3 Kinase-Glycogen Synthase Kinase 3 beta Pathway Mediates Bilobalide-Induced Reduction in Amyloid beta-Peptide
Authors: Shi, Chun; Zheng, Dong-dan; Wu, Feng-ming; Liu, Jun; Xu, Jie
Bilobalide (BB), a sesquiterpenoid extract of Ginkgo biloba leaves, has been demonstrated to have neuroprotective effects. The neuroprotective mechanisms were suggested to be associated with modulation of intracellular signaling cascades such as the phosphatidyl inositol 3-kinase (PI3K) pathway. Since some members of intracellular signalling pathways such as PI3K have been demonstrated to be involved in amyloid precursor protein (APP) processing, the present study investigated whether BB has an influence on the beta-secretase-mediated APP cleavage via PI3K-dependent pathway. Using HT22 cells and SAMP8 mice (a senescence-accelerated strain of mice), this study showed that BB treatment reduced generation of two beta-secretase cleavage products of APP, the amyloid beta-peptide (A beta) and soluble APP beta (sAPP beta), via PI3K-dependent pathway. Additionally, glycogen synthase kinase 3 beta (GSK3 beta) signaling might be involved in BB-induced A beta reduction as a downstream target of the activated PI3K pathway. BB showed no significant effects on beta-site APP cleaving enzyme 1 (BACE-1) or gamma-secretase but inhibited the beta-secretase activity of another protease cathepsin B, suggesting that BB-induced A beta reduction was probably mediated through modulation of cathepsin B rather than BACE-1. Similarly, inhibition of GSK3b did not affect BACE-1 activity but decreased cathepsin B activity, suggesting that the PI3K-GSK3 beta pathway was probably involved in BB-induced A beta reduction. Increasing evidence suggests that decreasing A beta production in the brain via modulation of APP metabolism should be beneficial for the prevention and treatment of Alzheimer's disease (AD). BB may offer such an approach to combat AD.
Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells
Authors: Tong, Jingshan; Wang, Peng; Tan, Shuai; Chen, Dongshi; Nikolovska-Coleska, Zaneta; Zou, Fangdong; Yu, Jian; Zhang, Lin
The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells. In this setting, Mcl-1 degradation was induced by a variety of multikinase inhibitor drugs, where it relied upon GSK3b phosphorylation and FBW7-dependent ubiquitination. Specific blockade by genetic knock-in (KI) abolished apoptotic responses and conferred resistance to kinase inhibitors. Mcl-1-KI also suppressed the antiangiogenic and anti-hypoxic effects of kinase inhibitors in the tumor microenvironment. Interestingly, these same inhibitors also induced the BH3-only Bcl-2 family protein PUMA, which is required for apoptosis. Degradation-resistant Mcl-1 bound and sequestered PUMA from other prosurvival proteins to maintain cell survival, which was abolished by small-molecule Mcl1 inhibitors. Our findings establish a pivotal role for Mcl-1 degradation in the response of colon cancer cells to targeted therapeutics, and they provide a useful rational platform to develop Mcl-1-targeting agents that can overcome drug resistance. (C) 2017 AACR.