Targeting the Eukaryotic Initiation Factor eIF4A to Overcome PDCD4 Tumor Suppressor Downregulation Against Breast Cancer Progression and Stemness

Subramanian, Alagu
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Despite advances in adjuvant-therapy, resistance to cancer therapeutics is common and requires novel approaches. Moreover, highly aggressive triple-negative breast cancers (TNBCs) lack effective targeted treatments. Deregulation of translation factors is associated with the increased proliferation of TNBC, heightened cancer stem cell (CSC) activity, the epithelial-to-mesenchymal transition (EMT) and poor patient outcomes. Thus, targeting translation regulatory factors upregulated in TNBC is a promising approach to developing novel treatments. Pateamine A (PatA), a natural marine macrodiolide product, inhibits RNA cap-dependent translation by sequestering the eukaryotic translation initiation factor eIF4A. eIF4A promotes the translation of polypurine-rich mRNA sequences, which are enriched within certain oncogenes. Here we report the anticancer efficacy of novel PatA analogs against breast cancer cell lines. The PatA analogs exhibited enhanced cytotoxicity to breast and colorectal cancers compared to non-cancerous cells measured by cell viability studies. Novel analogs show greater antiproliferative potency against models of TNBC than against human mammary epithelial cells (HMLE). To further elucidate eIF4A as a molecular target, we conducted analyses of patient tissues in the Cancer Genome Atlas (TCGA). Our analyses reveal the overexpression of eIF4A in tumors compared to normal tissues and gene correlation studies reveal the upregulation of key co-expressed tumor drivers including beta-catenin, fibronectin, and EMT markers such as SNAIL and SLUG. Further analyses show a downregulation of tumor suppressor protein PDCD4, an endogenous inhibitor of eIF4A, in tumors. We have generated eIF4A and PDCD4 shRNA knockdown cell lines to uncover the eIF4A-PDCD4 regulatory axis across breast adenocarcinoma cell types. We show that the loss of eIF4A attenuates the mesenchymal and stem-like phenotype of breast cancer stem cells revealed by phenotypic assays. Our results suggest that targeting eIF4A is an effective approach against highly proliferative and metastatic breast cancer types. The presented findings underscore the potential of the eIF4A-PDCD4 axis as a promising target and supports translational control as a viable approach against aggressive cancers.

Breast cancer., Translational control., Cancer proliferation., Cancer stem cells., Epithelial-to-mesenchymal transition.