Abstract
The eukaryotic translation initiation factor 4E (eIF4E) is considered as a key survival protein involved in cell cycle progression, transformation and apoptosis resistance. Herein, we demonstrate that medicinal plant derivative 3-AWA (from Withaferin A) suppressed the proliferation and metastasis of CaP cells through abrogation of eIF4E activation and expression via c-FLIP dependent mechanism. This translational attenuation prevents the de novo synthesis of major players of metastatic cascades viz. c-FLIP, c-Myc and cyclin D1. Moreover, the suppression of c-FLIP due to inhibition of translation initiation complex by 3-AWA enhanced FAS trafficking, BID and caspase 8 cleavage. Further ectopically restored c-Myc and GFP-HRas mediated activation of eIF4E was reduced by 3-AWA in transformed NIH3T3 cells. Detailed underlying mechanisms revealed that 3-AWA inhibited Ras-Mnk and PI3-AKT-mTOR, two major pathways through which eIF4E converges upon eIF4F hub. In addition to in vitro studies, we confirmed that 3-AWA efficiently suppressed tumor growth and metastasis in different mouse models. Given that 3-AWA inhibits c-FLIP through abrogation of translation initiation by co-targeting mTOR and Mnk-eIF4E, it (3-AWA) can be exploited as a lead pharmacophore for promising anti-cancer therapeutic development.
Highlights
The eukaryotic translation initiation factor 4E is considered as a key survival protein involved in cell cycle progression, transformation and apoptosis resistance
We examined the effects of 3-azido Withaferin A (3-AWA) mediated controlling of c-FLIP in metastasis/invasion prevention via inhibition of eIF4E phosphorylation involving in the protein translational apparatus
We demonstrate here that blocking of protein translation through the inhibition of eIF4E by 3-AWA has a profound effect on c-FLIP. c-FLIP forms an apoptosis inhibitory complex (AIC) by preventing both the formation of death-inducing signaling complex (DISC) and the activation of the caspase cascade27. c-FLIP isoforms (c-FLIPL, c-FLIPs and c-FLIPR) are reported to exert a role in the upregulation of many prosurvival and cytoprotective pathways, including ERK1, AKT and NF-kB28
Summary
Prostate cancer (CaP), a burden to the healthcare system, remains to be the second leading cause of cancer related deaths in the United States and patients with advanced prostate cancer show poor prognosis with severe disease recurrence[32]. 3-AWA treatment results in the blockage of translation initiation by regulating the expression and activation of eIF4E which in turn inhibits the expression of c-FLIP and the invasive behaviour of cancer cells. PI3K-AKT-mTOR pathway controls the activation of eIF4E oncogene by regulating the phosphorylation of key tumor suppressor protein 4EBP1. This depicted the potential of 3-AWA to inhibit eIF4E mediated cancer cell proliferation and metastasis The importance of this finding can be realized from the fact that over-expression of eIF4E and its hyperactivation by oncogenic alteration in the above mentioned pathways is associated with poor prognosis and relapse-free rate, especially in CaP patients[37]. 3-AWA has a potential to suppress the amplifying oncogenic signals and neoplastic capabilities of a cancer cell by preventing the eIF4F mediated reprogramming of cellular translation apparatus through the blockage of its upstream pathways via eIF4E. From a clinical cancer treatment point of view, this finding retrospect pharmacological importance of 3-AWA to control deregulated translational machinery
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