Abstract
Cancer death is a leading cause of global mortality. An estimated 14.1 million new cancer cases and 8.2 million cancer deaths occurred worldwide in 2012 alone. Cancer stem cells (CSCs) within tumors are essential for tumor metastasis and reoccurrence, the key factors of cancer lethality. Here we report that 4EGI-1, an inhibitor of the interaction between translation initiation factors eIF4E1 and eIF4G1 effectively inhibits breast CSCs through selectively reducing translation persistent in breast CSCs. Translation initiation factor eIF4E1 is significantly enhanced in breast CSCs in comparison to non-CSC breast cancer cells. 4EGI-1 presents increased cytotoxicity to breast CSCs compared to non-CSC breast cancer cells. 4EGI-1 promotes breast CSC differentiation and represses breast CSC induced tube-like structure formation of human umbilical vein endothelial cells (HUVECs). 4EGI-1 isomers suppress breast CSC tumorangiogenesis and tumor growth in vivo. In addition, 4EGI-1 decreases proliferation in and induces apoptosis into breast CSC tumor cells. Furthermore, 4EGI-1 selectively inhibits translation of mRNAs encoding NANOG, OCT4, CXCR4, c-MYC and VEGF in breast CSC tumors. Our study demonstrated that 4EGI-1 targets breast CSCs through selective inhibition of translation critical for breast CSCs, suggesting that selective translation initiation interference might be an avenue targeting CSCs within tumors.
Highlights
Cancer is a leading cause of mortality worldwide
We found that eIF4E1, but not eIF4E2, eIF4G1, eIF1A, eIF2α, or eIF5, is significantly increased in breast CSCs (BCSCs), in comparison to SKBR-3, MCF-7 and MDAMB-231 breast cancer cells and non-BCSCs of HMLER (CD44high/CD24low)SA cells (Fig.1A). eIF4E3 is hardly detectable in all these cancer cells
The above data indicate that 4EGI-1 presents increased cytotoxicity (>2-fold) to breast Cancer stem cells (CSCs) comparing to non-CSC breast cancer cells, which is in agreement with the significantly enhanced eIF4E1 in breast CSCs (Fig. 1A)
Summary
Cancer is a leading cause of mortality worldwide. Global cancer burden increased to 14.1 million new cases and 8.2 million cancer deaths in 2012 from 12.7 million and 7.6 million respectively, in 2008. Cancer metastasis and reoccurrence are the major resources of cancer lethality. Cancer stem cells (CSCs) form a subpopulation of cells within tumors and are essential for tumor dissemination and relapse[1]. The acquired properties that make CSCs adaptive to micro-environmental stresses and enhanced resistance to chemo-/radiationtherapy, present a challenge for targeting CSCs within tumors[2,3,4]. Heterogenetic CSCs are believed to acquire diverse adaptive changes in genetic, epigenetic, signal transduction, metabolic, transcriptional and translational levels[5, 6]. Translation is essential for all aspects of tumor evolution, including tumorigenesis, tumorangiogenesis, tumor growth, metastasis, CSC heterogeneity, and drug resistance[7, 8]. Protein synthesis is central for CSCs self-renewal, maintenance, differentiation, growth and dissemination
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