Hypoxia-inducible Factor-1α (HIF-1α) Promotes Cap-dependent Translation of Selective mRNAs through Up-regulating Initiation Factor eIF4E1 in Breast Cancer Cells under Hypoxia Conditions

Yi, Tongxun; Papadopoulos, Evangelos; Hagner, Patrick R.; Wagner, Gerhard

doi:10.1074/jbc.m113.471466

Cited by 57 publications

(61 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PDGFRA has also been linked to aggressive colorectal carcinomas (35). We did not observe noticeable differences in eIF4E protein levels across all five cell lines; however, 3-fold increases in eIF4E in a HIF1␣-dependent manner in a hypoxic breast cancer cell line suggest that cancerspecific mutation profiles may have different effects on the regulation of cap-dependent translation (36).…”

Section: Discussionmentioning

confidence: 51%

Human Cells Cultured under Physiological Oxygen Utilize Two Cap-binding Proteins to recruit Distinct mRNAs for Translation

Timpano¹,

Uniacke

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Translation initiation is a focal point of translational control and requires the binding of eIF4E to the 5 cap of mRNA. Under conditions of extreme oxygen depletion (hypoxia), human cells repress eIF4E and switch to an alternative cap-dependent translation mediated by a homolog of eIF4E, eIF4E2. This homolog forms a complex with the oxygen-regulated hypoxia-inducible factor 2␣ and can escape translation repression. This complex mediates cap-dependent translation under cell culture conditions of 1% oxygen (to mimic tumor microenvironments), whereas eIF4E mediates cap-dependent translation at 21% oxygen (ambient air). However, emerging evidence suggests that culturing cells in ambient air, or "normoxia," is far from physiological or "normal." In fact, oxygen in human tissues ranges from 1-11% or "physioxia." Here we show that two distinct modes of cap-dependent translation initiation are active during physioxia and act on separate pools of mRNAs. The oxygen-dependent activities of eIF4E and eIF4E2 are elucidated by observing their polysome association and the status of mammalian target of rapamycin complex 1 (eIF4E-dependent) or hypoxiainducible factor 2␣ expression (eIF4E2-dependent). We have identified oxygen conditions where eIF4E is the dominant capbinding protein (21% normoxia or standard cell culture conditions), where eIF4E2 is the dominant cap-binding protein (1% hypoxia or ischemic diseases and cancerous tumors), and where both cap-binding proteins act simultaneously to initiate the translation of distinct mRNAs (1-11% physioxia or during development and stem cell differentiation). These data suggest that the physioxic proteome is generated by initiating translation of mRNAs via two distinct but complementary cap-binding proteins.

show abstract

Section: Discussionmentioning

confidence: 51%

Human Cells Cultured under Physiological Oxygen Utilize Two Cap-binding Proteins to recruit Distinct mRNAs for Translation

Timpano¹,

Uniacke

2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…5A). Previously, we reported that 4EGI-1 inhibits translation of several oncogene mRNAs without affecting their transcription in multiple cancer cell lines at 24hr under normoxia and at 12hr under hypoxia conditions in vitro [16, 32]. These observations suggested that the indicated decreased protein levels in 4EGI-1 treated BCSC tumors were primarily, if not all, caused by selective inhibition of translation of mRNAs encoding these proteins.…”

Section: Resultsmentioning

confidence: 89%

4EGI-1 targets breast cancer stem cells by selective inhibition of translation that persists in CSC maintenance, proliferation and metastasis

Kabha

Papadopoulos

et al. 2014

Oncotarget

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…eIF4E is overexpressed in a variety of cancers and is a target of modern therapies (36)(37)(38)(39)(40)(41). Furthermore, eIF4E contributes to tumorsphere growth in hypoxic breast cancer cells (42). Indeed, eIF4E remains an attractive target to inhibit the growth of cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Cancer Cells Exploit eIF4E2-Directed Synthesis of Hypoxia Response Proteins to Drive Tumor Progression

et al. 2014

View full text Add to dashboard Cite

Human tumors display considerable diversity in their genetic makeup but share common physiologic attributes such as a hypoxic microenvironment that contribute to the malignant phenotype. Hypoxic cells switch from eukaryotic initiation factor 4E (eIF4E) to eIF4E2 cap-dependent translation to synthesize a portion of their proteins. Here, we show that genetically distinct human cancer cells exploit eIF4E2-directed protein synthesis to form cellular masses larger than approximately 0.15 mm, the diffusion limit of oxygen. Cancer cells depleted of eIF4E2 are indistinguishable from control cells under normoxic conditions, but are unable to survive and proliferate in low oxygen conditions. Activation of eIF4E2-directed translation is essential for cancer cells to form a hypoxic tumor core in in vitro spheroids and to form detectable tumors in in vivo xenograft assays. In contrast, the eIF4E-directed protein synthesis pathway alone cannot sustain cellular adaptation to hypoxia in vitro or confer tumorigenic potential in xenograft assays. These data demonstrate that the phenotypic expression of the cancer genome requires translation by the eIF4E2-directed hypoxic protein synthesis machinery. Cancer Res; 74(5); 1379-89. Ó2014 AACR.

show abstract

Hypoxia-inducible Factor-1α (HIF-1α) Promotes Cap-dependent Translation of Selective mRNAs through Up-regulating Initiation Factor eIF4E1 in Breast Cancer Cells under Hypoxia Conditions

Cited by 57 publications

References 62 publications

Human Cells Cultured under Physiological Oxygen Utilize Two Cap-binding Proteins to recruit Distinct mRNAs for Translation

Human Cells Cultured under Physiological Oxygen Utilize Two Cap-binding Proteins to recruit Distinct mRNAs for Translation

4EGI-1 targets breast cancer stem cells by selective inhibition of translation that persists in CSC maintenance, proliferation and metastasis

Cancer Cells Exploit eIF4E2-Directed Synthesis of Hypoxia Response Proteins to Drive Tumor Progression

Contact Info

Product

Resources

About