In:
Cellular Physiology and Biochemistry, S. Karger AG, Vol. 40, No. 5 ( 2016), p. 1013-1028
Abstract:
Background: Cancer cells are frequently addicted to deregulated oncogenic protein translation that usually arises as a consequence of increased signaling flux from eIF4F activation. The small molecule 4EG-I, a potent inhibitor of translation initiation through disrupting eIF4E/eIF4G interaction, has been shown to exert anticancer effects in animal models of human cancers. Methods: Here, we extensively investigated the anticancer activity of 4EGI-1 in human glioma U87 cells. The anti-cancer effects of 4EGI-1 were measured by cell viability, lactate dehydrogenase (LDH) release, TUNEL staining, flow cytometry and western blot analysis in vitro, and also examined in a U87 xenograft model in vivo. The potential underlying molecular mechanisms were investigated by measuring mitochondrial function and ER stress. Results: We found that 4EGI-1 impaired the assembly of the eIF4F complex and decreased the expression of the eIF4E regulated proteins. The results of TUNEL staining and flow cytometry showed that 4EGI-1 treatment induced apoptotic cell death in a dose-dependent manner. Furthermore, 4EGI-1-induced apoptosis in U87 cells was associated with mitochondrial dysfunction and activation of the intrinsic mitochondrial pathway, which was dependent on the induction of the pro-apoptotic protein Bax. In addition, 4EGI-1 treatment triggered ER stress, which was evidenced by morphological changes of ER lumen and ER calcium release, as well as the dose-dependent increases in the expression of ER stress related proteins. Moreover, knockdown of the ER chaperone GRP-78 through siRNA was shown to partially reverse the 4EGI-1-induced ER stress in U87 cells. In vivo, 4EGI-1 strongly inhibited growth of U87 glioma xenografts without any apparent organ related toxicities. Conclusion: These data indicate that the use of inhibitors that directly target the translation initiation complex eIF4F could represent a potential novel approach for human glioma therapy.
Type of Medium:
Online Resource
ISSN:
1015-8987
,
1421-9778
Language:
English
Publisher:
S. Karger AG
Publication Date:
2016
detail.hit.zdb_id:
1482056-0
SSG:
12
SSG:
15,3
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