Activated cap-mediated protein translation is found in many cancers (Mamane et al, 2004
). This activation is associated with the preferential translation of a limited number of transcripts responsible for cell proliferation and survival (Graff and Zimmer, 2003
; Rajasekhar et al, 2003
). Enhanced cap-mediated translation in cancer often occurs after either an overexpression of eIF4E, phosphorylation of eIF4E, or an inactivation of the 4E-BP1 repressor protein. In mesothelioma, the primary mechanism for elevated levels of cap-mediated translation seems to be a low-level expression of the 4E-BP1 repressor protein in conjunction with an activation of eIF4E (Patel et al, 2007
). This is in contrast to previous observations in cancers, such as non-small-cell lung cancer, in which both elevated levels of eIF4E and inactivation of the 4E-BP1 repressor protein are the primary mechanisms for activating the eIF4F complex (Jacobson et al, 2006
). This study shows that IGF-I stimulation of mesothelioma cells results in a similar hyperphosphorylation and inactivation of 4E-BP1 ().
It is well known that IGF-I stimulation of eukaryotic cells can lead to increased protein translation and contribute to the malignant potential in a variety of cell types (Miller and Yee, 2005
). In mesothelioma, IGF-I stimulation leads to the downstream activation of both PI3K/Akt and MAPK pathways (Hoang et al, 2004b
). The observation that IGF-I stimulation is associated with increased phosphorylation of 4E-BP1, allowing for an increase in the binding of the competing eIF4G protein, thus favouring protein translation, is not unexpected and is consistent with IGF-I-driven malignant growth in mesothelioma. In support of the function of the IGF-I axis in mesothelioma development, previous data demonstrate that malignant transformation of mesothelial cells in animal models requires an intact IGF1R molecule (Pass et al, 1996
). An intact and active IGF-I axis is necessary for both the development and propagation of mesothelioma cells.
Activation of IGF1R is associated with an increase in both mesothelioma cell proliferation and motility (Hoang et al, 2004b
). In this study, when cap-mediated protein translation was suppressed using the dominantly active mutant protein, 4E-BP1A37/A46
, mesothelioma cells showed diminished proliferation and motility even under conditions of IGF-I stimulation. IGF-I stimulation of mesothelioma cells also led directly to the activation of the cap-mediated translation complex. The importance of activation or repression of cap-mediated translation in mesothelioma is strongly emphasised by the observation that an enforced repression of translation in mesothelioma cells resulted in the near total loss of tumourigenic potential.
Our finding that cap-mediated protein translation is associated with IGF-I stimulation suggests that IGF1R inhibition is a very attractive therapeutic target in mesothelioma. IGF1R inhibitors are currently in clinical testing and seem to have potent in vitro
activity against mesothelioma cells (Whitson et al, 2006
). There are data that these agents are synergistic with cytotoxic chemotherapy, an observation that fits well with the pro-apoptotic effects known to accompany a repression of cap-mediated translation. We have previously shown that an enforced repression of cap-mediated activity can render cancer cells more susceptible to chemotherapeutic-induced apoptosis in non-small-cell lung cancer cells (Jacobson et al, 2006
). Suppressing IGF1R activation should have the same effect of reducing cap-mediated translation and enhancing chemosensitivity. In addition, the IGF1R-mediated activation of PI3K leads to an acquired resistance to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in A431 lung cancer cells (Guix et al, 2008
). The inhibition of both EGFR and IGF1R was required to reverse acquired in vitro
drug resistance. It is tempting to speculate that both oncogenic pathways converge upon the initiation of translation to mediate their oncogenic effects. If so, the initiation of cap-dependent translation would be an attractive target for new therapies, as it would potentially block the downstream signal of two major oncogenic pathways.
Novel agents are being developed for targeting eIF4E or for disabling the eIF4F molecular complex as a potential cancer therapy (Graff et al, 2007
). On the basis of these data demonstrating the important function that IGF-I stimulation and cap-mediated protein translation have in the malignant potential of mesothelioma cells, these therapies could prove to be promising treatments for mesothelioma. In the light of the findings that the effects of IGF1R activation in mesothelioma depend on the activation of the eIF4F complex, it will be interesting to combine IGF1R inhibition with agents designed to target cap-mediated translation.