A novel Bcr-Abl–mTOR–eIF4A axis regulates IRES-mediated translation of LEF-1

Abstract

Internal ribosome entry sites (IRESs) in cellular mRNAs direct expression of growth-promoting factors through an alternative translation mechanism that has yet to be fully defined. Lymphoid enhancer factor-1 (LEF-1), a Wnt-mediating transcription factor important for cell survival and metastasis in cancer, is produced via IRES-directed translation, and its mRNA is frequently upregulated in malignancies, including chronic myeloid leukaemia (CML). In this study, we determined that LEF1 expression is regulated by Bcr-Abl, the oncogenic protein that drives haematopoietic cell transformation to CML. We have previously shown that the LEF1 5′ untranslated region recruits a complex of proteins to its IRES, including the translation initiation factor eIF4A. In this report, we use two small molecule inhibitors, PP242 (dual mTOR (mammalian target of rapamycin) kinase inhibitor) and hippuristanol (eIF4A inhibitor), to define IRES regulation via a Bcr-Abl–mTOR–eIF4A axis in CML cell lines and primary patient leukaemias. We found that LEF1 and other IRESs are uniquely sensitive to the activities of Bcr-Abl/mTOR. Most notably, we discovered that eIF4A, an RNA helicase, elicits potent non-canonical effects on the LEF1 IRES. Hippuristanol inhibition of eIF4A stalls translation of IRES mRNA and triggers dissociation from polyribosomes. We propose that a combination drug strategy which targets mTOR and IRES-driven translation disrupts key factors that contribute to growth and proliferation in CML.

Glucagon and Insulin Cooperatively Stimulate Fibroblast Growth Factor 21 Gene Transcription by Increasing the Expression of Activating Transcription Factor 4

“…Second, fasting for 48 h causes an increase in hepatic PKA and mTORC1 signaling activity and ATF4 protein expression (30,55,56). Previous studies have shown that mTORC1 signaling activity induces both cap-dependent and cap-independent translation of selective internal ribosome entry site-containing mRNAs (57). We hypothesize that glucagon plus insulin stimulates ATF4 protein expression by enhancing mTORC1-dependent internal ribosome entry site translation of ATF4 mRNA (58).…”

Targeting RNA helicases in cancer: The translation trap

“…DEAD/H box family members have been found to facilitate IRES dependent translation of certain oncogenic mRNAs. Inhibition of eIF4A was found to block IRES dependent translation of EGFR[59] and c-MYC[58] under hypoxia and IRES dependent translation of the transcription factor LEF1[64] (Figure 2). DDX3 was found to have a stimulatory role on translation of the Hepatitis C Virus IRES[29, 30], potentially through its interaction with eIF4E.…”

Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

“…This dual inhibition of the mTOR complexes has also demonstrated tumor growth suppressive effects in a human AML xenograft mouse model [69]. Moreover, PP242 treatment reduced colony formation of leukemic progenitor cells derived from CML patients [76] Additionally, in AML models, OSI-027 has shown anti-leukemic effects in cell lines, as well as, in primary leukemic precursors from patients with AML. Importantly, when compared to rapamycin treatment, OSI-027 was able to completely block phosphorylation of 4E-BP1 in AML cells [40].…”