Abstract
Some retinoic acid metabolism blocking agents (RAMBAs) are known to exhibit a wide range of anticancer activities by mechanisms that are still not completely resolved. This study investigated the anticancer efficacy and mechanism(s) of novel RAMBA retinamides (RRs) in triple negative and Her-2 overexpressing breast cancer cells. Specifically, we examined the possibility that RRs affect the translational machinery in these breast cancer (BC) cells. Recent findings suggest that overexpression of eukaryotic translation initiation factor 4E (eIF4E) in breast cancers critically augments CAP-dependent mRNA translation and synthesis of proteins involved in cell growth, cell proliferation, invasion and apoptosis evasion. The oncogenic potential of eIF4E is strictly dependent on serine209 phosphorylation by upstream MAPK-interacting kinases (Mnks). Targeting Mnk/eIF4E pathway for blocking Mnk function and eIF4E phosphorylation is therefore a novel approach for treating BCs, particularly for Her2-positive and triple negative breast cancers that have no indications for endocrine therapy or effective treatment regimes. We report for the first time that the degradation of Mnk1 by RRs in BC cells blocks eIF4E phosphorylation and subsequently inhibits cell growth, colonization, invasion, and migration and induce apoptosis. Most importantly, the anticancer efficacy of RRs was mediated via degrading Mnk rather than inhibiting its kinase activity like Mnk inhibitors (cercosporamide and CGP57380). Furthermore, RRs potencies on peIF4E down-regulation and growth inhibition were superior to those of two clinically relevant retinoids and the Mnk inhibitors. Together our findings provide the first preclinical proof-of-concept of novel Mnk degrading agents for Mnk/eIF4E based therapeutic treatment of breast cancers.
Highlights
Despite significant advances toward targeted therapy and screening techniques, breast cancer remains the most frequently diagnosed female malignancy and leading cause of cancer-related deaths worldwide [1]
Since the present study has demonstrated that RAMBA retinamides (RRs) (VNLG-152) strongly inhibit cell proliferation, apoptosis evasion, invasion and migration in breast cancer (BC) cells by modulating several proteins including that of cyclin D1 (Fig. 1D), and Bcl-2 that are predominantly regulated by the mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks)/eukaryotic translation initiation factor 4E (eIF4E) pathway, we hypothesized that RRs might disrupt these downstream oncogenic events primarily by inhibiting Mnk/eIF4E pathway
Our results demonstrate that in human epidermal growth factor receptor 2 (Her2) overexpressing and triple-negative www.impactjournals.com/oncotarget breast cancers (TNBC) cells, RRs, especially, VNLG152 disrupt translation machinery resulting in inhibition of protein translation and downstream oncogenic events
Summary
Despite significant advances toward targeted therapy and screening techniques, breast cancer remains the most frequently diagnosed female malignancy and leading cause of cancer-related deaths worldwide [1]. Selective amplification and/ or overexpression of human epidermal growth factor receptor 2 (Her2) is found in approximately 25–30% of all primary breast cancers. Her plays a critical role in regulating cell proliferation, adhesion, motility, and survival, and Her overexpression results in aggressive tumor behavior, clinical resistance and poor prognosis [2]. Several breast cancer studies have identified numerous genes such as p53, PIK3CA, AKT1, PTEN, and EGFR to be commonly mutated in breast cancers. Activating mutations in these genes promote aberrant activation of certain signaling cascades and in turn tumor growth via up-regulation of key oncogenic proteins [2]
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