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WX20120108, a novel IAP antagonist, induces tumor cell autophagy via activating ROS-FOXO pathway.

ABSTRACT: Recently, inhibitor of apoptosis proteins (IAPs) and some IAP antagonists were found to regulate autophagy, but the underlying mechanisms remain unclear. WX20120108 is an analogue of GDC-0152 (a known IAP antagonist) and displays more potent anti-tumor and autophagy-regulating activity in tumor cells, we investigated the regulatory mechanisms underlying WX20120108-induced autophagy. Using molecular docking and fluorescence polarization anisotropy (FPA) competitive assay, we first demonstrated that WX20120108, acting as an IAP antagonist, bound to the XIAP-BIR3, XIAP BIR2-BIR3, cIAP1 BIR3, and cIAP2 BIR3 domains with high affinities. In six cancer cell lines, WX20120108 inhibited the cell proliferation with potencies two to ten-fold higher than that of GDC-0152. In HeLa and MDA-MB-231 cells, WX20120108 induced caspase-dependent apoptosis and activated TNF?-dependent extrinsic apoptosis. On the other hand, WX20120108 induced autophagy in HeLa and MDA-MB-231 cells in dose- and time-dependent manners. We revealed that WX20120108 selectively activated Foxo3, evidenced by Foxo3 nuclear translocation in both gene modified cell line and HeLa cells, as well as the upregulated expression of Foxo3-targeted genes (Bnip3, Pik3c3, Atg5, and Atg4b), which played a key role in autophagy initiation. WX20120108-induced autophagy was significantly suppressed when Foxo3 gene was silenced. WX20120108 dose-dependently increased the generation of reactive oxygen species (ROS) in HeLa cells, and WX20120108-induced Foxo3 activation was completely blocked in the presence of catalase, a known ROS scavenger. However, WX20120108-induced ROS generation was not affected by cIAP1/2 or XIAP gene silencing. In conclusion, WX20120108-induced autophagy relies on activating ROS-Foxo3 pathway, which is independent of IAPs. This finding provides a new insight into the mechanism of IAP antagonist-mediated regulation of autophagy.

SUBMITTER: Ding R

PROVIDER: S-EPMC6889436 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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WX20120108, a novel IAP antagonist, induces tumor cell autophagy via activating ROS-FOXO pathway.

Ding Rui R Wang Xin X Chen Wei W Li Zhi Z Wei Ai-Li AL Wang Qing-Bin QB Nie Ai-Hua AH Wang Li-Li LL

Acta pharmacologica Sinica 20190717 11

Recently, inhibitor of apoptosis proteins (IAPs) and some IAP antagonists were found to regulate autophagy, but the underlying mechanisms remain unclear. WX20120108 is an analogue of GDC-0152 (a known IAP antagonist) and displays more potent anti-tumor and autophagy-regulating activity in tumor cells, we investigated the regulatory mechanisms underlying WX20120108-induced autophagy. Using molecular docking and fluorescence polarization anisotropy (FPA) competitive assay, we first demonstrated th ...[more]

PMID: 31316176

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Project description:Background: Doxorubicin (Dox) can induce endotheliotoxicity and damage the vascular endothelium (VE). The most principle mechanism might be excess reactive oxygen species (ROS) generation. Nevertheless, the characteristics of ROS generation, downstream mechanisms, and target organelles in Dox-induced endotheliotoxicity have yet to be elucidated. Methods and Results: In order to explore the related problems, the VE injury models were established in mice and human umbilical vein endothelial cells (HUVECs) by Dox-induced endotheliotoxicity. Results showed that the activities of lactate dehydrogenase (LDH) and creatine kinase of mice's serum increased after injected Dox. The thoracic aortic strips' endothelium-dependent dilation was significantly impaired, seen noticeable inflammatory changes, and brown TUNEL-positive staining in microscopy. After Dox-treated, HUVECs viability lowered, LDH and caspase-3 activities, and apoptotic cells increased. Both intracellular/mitochondrial ROS generation significantly increased, and intracellular ROS generation lagged behind mitochondria. HUVECs treated with Dox plus ciclosporin A (CsA) could basically terminate ROS burst, but plus edaravone (Eda) could only delay or inhibit, but could not completely cancel ROS burst. Meanwhile, the expression of endothelial nitric oxide synthase (eNOS) decreased, especially phosphorylation of eNOS significantly. Then nitric oxide content decreased, the mitochondrial function was impaired, mitochondrial membrane potential (MMP) impeded, mitochondrial swelled, mitochondrial permeability transition pore (mPTP) was opened, and cytochrome C was released from mitochondria into the cytosol. Conclusion: Dox produces excess ROS in the mitochondria, thereby weakens the MMP, opens mPTP, activates the ROS-induced ROS release mechanism, induces ROS burst, and leads to mitochondrial dysfunction, which in turn damages VE. Therefore, interrupting any step of the cycles, as mentioned above can end the related vicious cycle and prevent the occurrence and development of injury.

Dataset Information

WX20120108, a novel IAP antagonist, induces tumor cell autophagy via activating ROS-FOXO pathway.

Publications

WX20120108, a novel IAP antagonist, induces tumor cell autophagy via activating ROS-FOXO pathway.

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