Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness

Abstract

Breast cancer stem cells (BCSCs) are intrinsically chemoresistant and capable of self-renewal. Following chemotherapy, patients can develop minimal residual disease due to BCSCs which can repopulate into a relapsed tumor. Therefore, it is imperative to co-target BCSCs along with the bulk tumor cells to achieve therapeutic success and prevent recurrence. So, it is vital to identify actionable molecular targets against both BCSCs and bulk tumor cells. Previous findings from our lab and others have demonstrated that inhibition of the emerging drug target eIF4A with Rocaglamide A (RocA) was efficacious against triple-negative breast cancer cells (TNBC). RocA specifically targets the pool of eIF4A bound to the oncogenic mRNAs that requires its helicase activity for their translation. This property enables specific targeting of tumor cells. The efficacy of RocA against BCSCs is unknown. In this study, we postulated that eIF4A could be a vulnerable node in BCSCs. In order to test this, we generated a paclitaxel-resistant TNBC cell line which demonstrated an elevated level of eIF4A along with increased levels of cancer stemness markers (ALDH activity and CD44), pluripotency transcription factors (SOX2, OCT4, and NANOG) and drug transporters (ABCB1, ABCG2, and ABCC1). Furthermore, genetic ablation of eIF4A resulted in reduced expression of ALDH1A1, pluripotency transcription factors and drug transporters. This pointed out that eIF4A is likely associated with selected set of proteins that are critical to BCSCs, and hence targeting eIF4A may eliminate BCSCs. Therefore, we isolated BCSCs from two TNBC cell lines: MDA-Bone-Un and SUM-159PT. Following RocA treatment, the self-renewal ability of the BCSCs was significantly reduced as determined by the efficiency of the formation of primary and secondary mammospheres. This was accompanied by a reduction in the levels of NANOG, OCT4, and drug transporters. Exposure to RocA also induced cell death of the BCSCs as evaluated by DRAQ7 and cell viability assays. RocA treatment induced apoptosis with increased levels of cleaved caspase-3. Overall, we identified that RocA is effective in targeting BCSCs, and eIF4A is an actionable molecular target in both BCSCs and bulk tumor cells. Therefore, anti-eIF4A inhibitors could potentially be combined synergistically with existing chemo-, radio- and/or immunotherapies.

Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells

“…Importantly, eIF4A1 and eIF4E were found to be independent predictors of poor outcome in ER-negative breast cancer [13]. Recently, we indicated a role for eIF4A1 in facilitating paclitaxel resistance in TNBC cell lines [14].…”

Whole-transcriptome Analysis of Fully Viable Energy Efficient Glycolytic-null Cancer Cells Established by Double Genetic Knockout of Lactate Dehydrogenase A/B or Glucose-6-Phosphate Isomerase

“…While the loss of ALDHs coincides with complete loss of glucose utilization in both KO clones, the causal effect, if any, between these two events will need further investigation. Future studies will be needed to confirm if LDHA/B inhibitors could be combined with ALDH inhibitors to evoke a more significant chemotherapeutic effect of drugs and radiation (48), and could be explored with ALDH inhibitors such as (-)epigallocatechin gallate (65,66), rocaglamide A (67), NCT-501 (67), and ellagic acid (68).…”

MicroRNA‐148a‐3p suppresses epithelial‐to‐mesenchymal transition and stemness properties via Wnt1‐mediated Wnt/β‐catenin pathway in pancreatic cancer

“…In 2007, Li et al 37 firstly identified pancreatic CSCs using CD44 (+)CD24(+)ESA(+) as surface markers. Since then, pancreatic CSCs have been recognized in succession by using various surface markers, including CD133, 29 CD44, 38 CD24, c‐met and ALDH 39 . In the present study, we identified pancreatic CSCs using CD133 as a surface marker and found that the proportion of CSCs in PC cells was significantly elevated as to normal HPDE cells.…”