Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap

Abstract

The eukaryotic translation initiation factor eIF4E is deregulated in many human cancers, and its overexpression in cells leads to malignant transformation. Oncogenic properties of eIF4E are directly linked to its ability to bind 7-methyl guanosine of the 5 mRNA. Here, we observe that the antiviral guanosine analogue ribavirin binds to eIF4E with micromolar affinity at the functional site used by 7-methyl guanosine mRNA cap, competes with eIF4E:mRNA binding, and, at low micromolar concentrations, selectively disrupts eIF4E subcellular organization and transport and translation of mRNAs posttranscriptionally regulated by eIF4E, thereby reducing levels of oncogenes such as cyclin D1. Ribavirin potently suppresses eIF4E-mediated oncogenic transformation of murine cells in vitro, of tumor growth of a mouse model of eIF4E-dependent human squamous cell carcinoma in vivo, and of colony formation of eIF4E-dependent acute myelogenous leukemia cells derived from human patients. These findings describe a specific, potent, and unforeseen mechanism of action of ribavirin. Quantum mechanical and NMR structural studies offer directions for the development of derivatives with improved cytostatic and antiviral properties. In all, ribavirin's association with eIF4E may provide a pharmacologic means for the interruption of posttranscriptional networks of oncogenes that maintain and enhance neoplasia and malignancy in human cancer.cancer ͉ drug ͉ virus ͉ oncogenic network W hereas the precise causes of neoplasia and malignancy are known only for a few human cancers, deregulated tumor suppressors and oncogenes that maintain and enhance the malignant phenotype are becoming relatively well described (1, 2). Among these molecules are tumor suppressors like p53, Rb, and APC and oncogenes such as myc, cyclin D1, and eIF4E. Their interactions constitute a network of self-reinforcing feedback loops, whereby inactivation of principal elements can lead to reversal and at times even sustained loss of neoplastic phenotype (3, 4). eIF4E is overexpressed in a wide variety of malignant cell lines and primary human tumors such as carcinomas of the breast (5), colon (6), and head and neck (7), non-Hodgkin's lymphomas (8), and chronic and acute M4͞M5 myelogenous leukemias (9). Consistently, even moderate overexpression of eIF4E in rodent cells leads to deregulated proliferation and malignant transformation (10). eIF4E is essential for growth and survival of eukaryotes by acting at a critical step of cap-dependent translation and recruiting transcripts to the ribosome as a result of a specific interaction with the 5Ј 7-methyl guanosine (m 7 G) mRNA cap (11). It is important to stress that, although the interaction of eIF4E with the 5Ј mRNA cap is required for initiation of translation of cap-dependent mRNAs, up-regulation of eIF4E does not increase translation of all cap-dependent transcripts, but only of a specific subset of eIF4E-sensitive transcripts, as described below.As much as 70% of eIF4E is present in the nuclei of mammalian cells, where it i...

Controlling Gene Expression through RNA Regulons: The Role of the Eukaryotic Translation Initiation Factor eIF4E

“…Importantly, studies in primary human leukemia specimens suggest that cancer cells overexpressing eIF4E develop an oncogene dependency on eIF4E, making these cells more sensitive to eIF4E inhibition. 31 This type of oncogene "addiction" is similar to observations with other oncogenes such as Her2 and PI3K. 32,33 We serendipitously discovered that a well known anti-viral drug, ribavirin, acts as a cap analogue.…”

“…Ribavirin treatment impedes eIF4E mediated oncogenic transformation in NIH3T3 cells. 31 Treatment of xenograft mouse models of eIF4E dependent tumours leads to reduced tumour sizes versus untreated controls in our studies with head and neck squamuous cell carcinomas. 31 In mouse models of metastases by Hairisi and colleagues, ribavirin reduced liver metastatic disease.…”

“…31,34 Further, ribavirin impedes both eIF4E's function in 4E-SE mRNA export and in translation of eIF4E sensitive transcripts. 31 Consistent with its biochemical activity, ribavirin inhibits the growth promoting activities of eIF4E. Ribavirin treatment impedes eIF4E mediated oncogenic transformation in NIH3T3 cells.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…149 The antiviral drug ribavirin can block the binding of eIF4E to mRNA. 150,151 Thus, the effects of this compound were examined in some patients with relapsed M4/M5 AML who were no longer eligible for chemotherapy. Although the number of patients in this preliminary trial were low (n ¼ 11), one complete and two partial responders were observed.…”

GC-selective DNA-binding antibiotic, Mithramycin A, reveals multiple points of control in the regulation of Hdm2 protein synthesis

“…The translation initiation factor eIF4E for example has, in addition to its well-described role in the cytoplasm, a nuclear role in the regulation of export of a subset of mRNAs including cyclin D1 (Culjkovic et al, 2005). This function may be involved in the oncogenic function of eIF4E, and both this (Kentsis et al, 2004), and possibly other (O'Shea et al, 2004), selective mRNA export pathways are potential targets for cancer therapy. The proteins involved in the selective export of hdm2 mRNA remain to be identified, however our finding that hdm2 mRNA export is not only dependent upon MEK kinase activity, but is also sensitive to the anti-tumour antibiotic MA in a MEKindependent manner, not only highlight the importance of regulated mRNA export in controlling Hdm2 synthesis, but should also prove useful in the elucidation of its mechanism.…”