Upregulated Cyclin B1/CDK1 Mediates Apoptosis Following 2-Methoxyestradiol-Induced Mitotic Catastrophe: Role of Bcl-XL Phosphorylation

Publication date: Available online 22 February 2019Source: SteroidsAuthor(s): Hye Joung Choi, Bao Ting ZhuAbstract2-Methoxyestradiol is an endogenous nonpolar metabolite of 17β-estradiol with a strong antitubulin activity. Earlier we showed that 2-methoxyestradiol increases the level and activity of cyclin B1/CDK1, which subsequently induces mitotic prometaphase arrest. In the present study, we demonstrate that upregulation of cyclin B1/CDK1 is responsible for the increased phosphorylation of the anti-apoptotic proteins Bcl-2 and Bcl-XL in 2-methoxyestradiol-induced, mitotically-arrested cancer cells. Additional analysis shows that only the increase in phosphorylation of Bcl-XL, but not Bcl-2, is associated with activation of the mitochondrial cell death pathway. We find that MAD2 is an important upstream mediator of the antitubulin function of 2-methoxyestradiol, resulting in activation of the MKK4-JNK1 pathway. JNK1 activation then leads to cyclin B1/CDK1 upregulation, which further increases Bcl-2 and Bcl-XL phosphorylation. Together, these results indicate that cyclin B1/CDK1 upregulation in cancer cells undergoing 2-methoxyestradiol-induced mitotic catastrophe causes apoptosis via Bcl-XL phosphorylation.Graphical abstract
Source: Steroids - Category: Drugs & Pharmacology Source Type: research