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Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness
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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909344/ https://www.ncbi.nlm.nih.gov/pubmed/31867270 http://dx.doi.org/10.3389/fonc.2019.01311 |
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author | Sridharan, Sangita Robeson, Megan Bastihalli-Tukaramrao, Diwakar Howard, Cory M. Subramaniyan, Boopathi Tilley, Augustus M. C. Tiwari, Amit K. Raman, Dayanidhi |
author_facet | Sridharan, Sangita Robeson, Megan Bastihalli-Tukaramrao, Diwakar Howard, Cory M. Subramaniyan, Boopathi Tilley, Augustus M. C. Tiwari, Amit K. Raman, Dayanidhi |
author_sort | Sridharan, Sangita |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6909344 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-69093442019-12-20 Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness Sridharan, Sangita Robeson, Megan Bastihalli-Tukaramrao, Diwakar Howard, Cory M. Subramaniyan, Boopathi Tilley, Augustus M. C. Tiwari, Amit K. Raman, Dayanidhi Front Oncol Oncology 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. Frontiers Media S.A. 2019-12-06 /pmc/articles/PMC6909344/ /pubmed/31867270 http://dx.doi.org/10.3389/fonc.2019.01311 Text en Copyright © 2019 Sridharan, Robeson, Bastihalli-Tukaramrao, Howard, Subramaniyan, Tilley, Tiwari and Raman. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Sridharan, Sangita Robeson, Megan Bastihalli-Tukaramrao, Diwakar Howard, Cory M. Subramaniyan, Boopathi Tilley, Augustus M. C. Tiwari, Amit K. Raman, Dayanidhi Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness |
title | Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness |
title_full | Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness |
title_fullStr | Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness |
title_full_unstemmed | Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness |
title_short | Targeting of the Eukaryotic Translation Initiation Factor 4A Against Breast Cancer Stemness |
title_sort | targeting of the eukaryotic translation initiation factor 4a against breast cancer stemness |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6909344/ https://www.ncbi.nlm.nih.gov/pubmed/31867270 http://dx.doi.org/10.3389/fonc.2019.01311 |
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