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• Research Paper pp undefined-undefined

  Celatrol impairs tumor growth by modulating the CIP2A-GSK3β-MCL-1 axis in gastric cancer cells

  Relevance score: 8.363927

  Jin Wu, Feng Ye, Tao Xu

  Keywords: celastrol, gastric cancer, CIP2A

  Published in Aging on Invalid Date

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  Backgroud/Aim: High Cancerous Inhibitor of PP2A (CIP2A) expression has been reported in solid and hematologic malignancies and is inversely associated with prognosis in Gastric Cancer, the non-small cell lung cancer, et al. CIP2A can be a drug target for the development of novel anti-gastric cancer agent. Our study was designed to explore the anti-cancer effect of celastrol, a small natural compound, and whether it has an anti-proliferative effect through inducing CIP2A degradation against gastric cancer cells.

  Materials and Methods: Employing human gastric cancer cells AGS and BCG-823 cells, the effects of celastrol on cell proliferation, apoptosis and cell cycle was specifically investigated via Annexin V-FITC/PI staining and CCK8 assay. The functional association between celastral and CIP2A was evaluated by using CIP2A knockdown and overexpression technique. The mechanism of underlying celastrol-triggering anti-gastric cancer effect was detected by real-time PCR and western blot analysis.

  Results: Celastral concentration- and time-dependently induced CIP2A degradation and led to gastric cancer cell apoptosis. More in depth studies revealed specific activation of Protein phosphatase 2A (PP2A)-GSK3β-MCL-1 signaling pathway was involved in pro-apoptosis effect of celastrol, due to celastrol-triggering degradation of CIP2A, which mainly suppressed PP2A activity.

  Conclusion: Our findings highlight that celastrol has therapeutic potential via inducing apoptosis of gastric cancer cells.

• Research Paper pp undefined-undefined

  Chronic stress induces Alzheimer’s disease-like pathologies through DNA damage-Chk1-CIP2A signaling

  Relevance score: 6.4693017

  Zhuoqun Wang, Lun Zhang, Jiayu Yang, Yi Zeng, Chengke Su, Mengdong Yao, Huiliang Zhang, Wenting Hu, Yi Liu, Yiwen Lai, Xiaochuan Wang, Ji Zeng, Rong Liu

  Keywords: stress, Alzheimer’s disease, DNA damage, Chk1, CIP2A

  Published in Aging on Invalid Date

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  Stress is an important initiating factor in promoting Alzheimer’s disease (AD) pathogenesis. However, the mechanism by which stress induces AD-like cognitive impairment remains to be clarified. Here, we demonstrate that DNA damage is increased in stress hormone Corticotropin-releasing factor (CRF)-treated cells and in brains of mice exposed to chronic restraint stress. Accumulation of DNA damage drives activation of cell cycle checkpoint protein kinase 1 (Chk1), upregulation of cancerous inhibitor of PP2A (CIP2A), tau hyperphosphorylation, and Aβ overproduction, eventually resulting in synaptic impairment and cognitive deficits. Pharmacological intervention targeting Chk1 by specific inhibitor and DNA damage by vitamin C, suppress DNA damage-Chk1-CIP2A signaling pathway in chronic stress animal model, which in turn attenuate AD-like pathologies, synaptic impairments and cognitive deficits. Our study uncovers a novel molecular mechanism of stress-induced AD-like pathologies, and provides effective preventive and therapeutic strategies targeting this signaling pathway.