ACT001 reverses resistance of prolactinomas via AMPK-mediated EGR1 and mTOR pathway

2021 ◽  
Author(s):  
Junhao Zhu ◽  
Chao Tang ◽  
Zixiang Cong ◽  
Feng Yuan ◽  
Xiangming Cai ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Drug Resistance ◽  
Cell Death ◽  
Signaling Pathway ◽  
Intracellular Reactive Oxygen Species ◽  
Gh3 Cells ◽  
Oxygen Species ◽  
Mtor Signaling Pathway ◽  
First Choice ◽  
Therapeutic Compound

Dopamine agonist (DA) is the first choice for the treatment of prolactinomas and drug resistance is unavoidable during treatment due to the heterogeneity of tumors. The two prolactinoma cell lines (GH3 cells and MMQ cells) were found to have different sensitivity and responding modes to the cabergoline (CAB) and bromocriptine (BRC). In this research, we disclosed the capability of ACT001, a derivative of parthenolide analogues, to activate AMPK by increasing the intracellular reactive oxygen species (ROS) level and AMP/ATP ratio to reverse DA-resistance through dual pathways in prolactinoma cells. The results indicated that ACT001 could reverse the CAB-resistance in GH3 cells by inhibiting the mTOR signaling pathway mainly inducing cell death through autophagy and reverse the BRC-resistance in MMQ cells by activating the EGR1 signaling pathway mainly inducing cell death through apoptosis. Our results suggested that ACT001 is a promising therapeutic compound for treating DA-resistant prolactinomas.

scholarly journals A Chemogenomic Screen in Saccharomyces cerevisiae Uncovers a Primary Role for the Mitochondria in Farnesol Toxicity and Its Regulation by the Pkc1 Pathway

2006 ◽  
Vol 282 (7) ◽  
pp. 4868-4874 ◽  
Author(s):  
Gregory D. Fairn ◽  
Kendra MacDonald ◽  
Christopher R. McMaster
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Electron Transport ◽  
Signaling Pathway ◽  
Electron Transport Chain ◽  
Reactive Oxygen ◽  
Complex Iii ◽  
Oxygen Species ◽  
Transport Chain

The isoprenoid farnesol has been shown to preferentially induce apoptosis in cancerous cells; however, the mode of action of farnesol-induced death is not established. We used chemogenomic profiling using Saccharomyces cerevisiae to probe the core cellular processes targeted by farnesol. This screen revealed 48 genes whose inactivation increased sensitivity to farnesol. The gene set indicated a role for the generation of oxygen radicals by the Rieske iron-sulfur component of complex III of the electron transport chain as a major mediator of farnesol-induced cell death. Consistent with this, loss of mitochondrial DNA, which abolishes electron transport, resulted in robust resistance to farnesol. A genomic interaction map predicted interconnectedness between the Pkc1 signaling pathway and farnesol sensitivity via regulation of the generation of reactive oxygen species. Consistent with this prediction (i) Pkc1, Bck1, and Mkk1 relocalized to the mitochondria upon farnesol addition, (ii) inactivation of the only non-essential and non-redundant member of the Pkc1 signaling pathway, BCK1, resulted in farnesol sensitivity, and (iii) expression of activated alleles of PKC1, BCK1, and MKK1 increased resistance to farnesol and hydrogen peroxide. Sensitivity to farnesol was not affected by the presence of the osmostabilizer sorbitol nor did farnesol affect phosphorylation of the ultimate Pkc1-responsive kinase responsible for controlling the cell wall integrity pathway, Slt2. The data indicate that the generation of reactive oxygen species by the electron transport chain is a primary mechanism by which farnesol kills cells. The Pkc1 signaling pathway regulates farnesol-mediated cell death through management of the generation of reactive oxygen species.

scholarly journals 8-Gingerol Ameliorates Myocardial Fibrosis by Attenuating Reactive Oxygen Species, Apoptosis, and Autophagy via the PI3K/Akt/mTOR Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yucong Xue ◽  
Muqing Zhang ◽  
Miaomiao Liu ◽  
Yu Liu ◽  
Li Li ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Signaling Pathway ◽  
Myocardial Fibrosis ◽  
Marked Decrease ◽  
Mtor Signaling ◽  
Ros Generation ◽  
Oxygen Species ◽  
Mtor Signaling Pathway ◽  
Weight Index ◽  
Related Proteins

8-gingerol (8-Gin) is the series of phenolic substance that is extracted from ginger. Although many studies have revealed that 8-Gin has multiple pharmacological properties, the possible underlying mechanisms of 8-Gin against myocardial fibrosis (MF) remains unclear. The study examined the exact role and potential mechanisms of 8-Gin against isoproterenol (ISO)-induced MF. Male mice were intraperitoneally injected with 8-Gin (10 and 20 mg/kg/d) and concurrently subcutaneously injected with ISO (10 mg/kg/d) for 2 weeks. Electrocardiography, pathological heart morphology, myocardial enzymes, reactive oxygen species (ROS) generation, degree of apoptosis, and autophagy pathway-related proteins were measured. Our study observed 8-Gin significantly reduced J-point elevation and heart rate. Besides, 8-Gin caused a marked decrease in cardiac weight index and left ventricle weight index, serum levels of creatine kinase and lactate dehydrogenase (CK and LDH, respectively), ROS generation, and attenuated ISO-induced pathological heart damage. Moreover, treatment with 8-Gin resulted in a marked decrease in the levels of collagen types I and III and TGF-β in the heart tissue. Our results showed 8-Gin exposure significantly suppressed ISO-induced autophagosome formation. 8-Gin also could lead to down-regulation of the activities of matrix metalloproteinases-9 (MMP-9), Caspase-9, and Bax protein, up-regulation of the activity of Bcl-2 protein, and alleviation of cardiomyocyte apoptosis. Furthermore, 8-Gin produced an obvious increase in the expressions of the PI3K/Akt/mTOR signaling pathway-related proteins. Our data showed that 8-Gin exerted cardioprotective effects on ISO-induced MF, which possibly occurred in connection with inhibition of ROS generation, apoptosis, and autophagy via modulation of the PI3K/Akt/mTOR signaling pathway.

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