Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma Journal Article
| Authors: | Schatz, J. H.; Oricchio, E.; Wolfe, A. L.; Jiang, M.; Linkov, I.; Maragulia, J.; Shi, W.; Zhang, Z.; Rajasekhar, V. K.; Pagano, N. C.; Porco, J. A.; Teruya-Feldstein, J.; Rosen, N.; Zelenetz, A. D.; Pelletier, J.; Wendel, H. G. |
| Article Title: | Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma |
| Abstract: | New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on cap-dependent translation, and genetic or pharmacological blockade of the translation initiation complex is highly effective against these tumors. The therapeutic effect of blocking cap-dependent translation is mediated, at least in part, by decreased production of short-lived oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves. Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors. © 2011 Schatz et al. |
| Keywords: | signal transduction; protein kinase b; cancer chemotherapy; controlled study; unclassified drug; oncoprotein; human cell; doxorubicin; nonhuman; drug targeting; flow cytometry; antineoplastic agent; translation initiation; mouse; enzyme inhibition; protein kinase inhibitor; animal experiment; animal model; enzyme activation; chemosensitivity; nonhodgkin lymphoma; cancer cell; lymphoma cell; lymphoma; cyclin d1; oncogene c myc; initiation factor 4a; protein kinase; follicular lymphoma; rapamycin; mammalian target of rapamycin complex 1; silvestrol; pim kinase; sgi 1776 |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 208 |
| Issue: | 9 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2011-08-29 |
| Start Page: | 1799 |
| End Page: | 1807 |
| Language: | English |
| DOI: | 10.1084/jem.20110846 |
| PUBMED: | 21859846 |
| PROVIDER: | scopus |
| PMCID: | PMC3171093 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 9 December 2011" - "CODEN: JEMEA" - "Source: Scopus" |
