Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma

Cancer Biology and Genetics Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/2011; 208(9):1799-807. DOI: 10.1084/jem.20110846
Source: PubMed


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.

Download full-text


Available from: Neal Rosen, Mar 10, 2014
  • Source
    • "Mammalian expression constructs that were generated are described in detail in figures and in Supporting Information. SypHluorin was kindly provided by Yongling Zhu (Salk Institute) (Zhu and Stevens, 2008), and 4E-BP1–4Ala carrying alanine substitutions at four phosphorylation sites (Thr37, Thr46, Ser65, and Thr70), by Dr. Hans G. Wendel (Memorial Sloan-Kettering Cancer Center) (Schatz et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Axonal growth cones synthesize proteins during development and in response to injury in adult animals. Proteins locally translated in axons are used to generate appropriate responses to guidance cues, contribute to axon growth, and can serve as retrograde messengers. In addition to growth cones, mRNAs and translational machinery are also found along the lengths of axons where synapses form en passant, but contributions of intra-axonal translation to developing synapses are poorly understood. Here, we engineered a subcellular-targeting translational repressor to inhibit mRNA translation in axons, and we used this strategy to investigate presynaptic contributions of cap-dependent protein translation to developing CNS synapses. Our data show that intra-axonal mRNA translation restrains synaptic vesicle recycling pool size and that one target of this regulation is p35, a Cdk5 activating protein. Cdk5/p35 signaling regulates the size of vesicle recycling pools, p35 levels diminish when cap-dependent translation is repressed, and restoring p35 levels rescues vesicle recycling pools from the effects of spatially targeted translation repression. Together our findings show that intra-axonal synthesis of p35 is required for normal vesicle recycling in developing neurons, and that targeted translational repression provides a novel strategy to investigate extrasomal protein synthesis in neurons. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.
    Developmental Neurobiology 03/2014; 74(3). DOI:10.1002/dneu.22154 · 3.37 Impact Factor
  • Source
    • "PIM2 is overexpressed in several B-cell cancers, including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, and myeloma (Cohen et al., 2004; Huttmann et al., 2006). PIM kinases are under investigation as targets for pharmacological inhibition in hematological cancers (Schatz et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of the forkhead transcription factor CHES1, also known as FOXN3, is reduced in many types of cancers. We show here that CHES1 decreased protein synthesis and cell proliferation in tumor cell lines but not in normal fibroblasts. Conversely shRNA-mediated depletion of CHES1 increased tumor cell proliferation. Growth suppression was dependent on the CHES1 forkhead DNA binding domain and correlated with the nuclear localization of CHES1. CHES1 repressed the expression of multiple genes including the kinases PIM2 and DYRK3, which regulate protein biosynthesis, and a number of genes in cilium biogenesis. CHES1 binds directly to the promoter of PIM2 and in cells expressing CHES1 the levels of PIM2 were reduced as well as the phosphorylation of the PIM2 target 4EBP1. Overexpression of PIM2 or eIF4E partially reversed the antiproliferative effect of CHES1 indicating that PIM2 and protein biosynthesis are important targets of the antiproliferative effect of CHES1. In several human hematopoietic cancers, CHES1 and PIM2 expression are inversely correlated suggesting that repression of PIM2 by CHES1 is clinically relevant.
    Molecular biology of the cell 01/2014; 25(5). DOI:10.1091/mbc.E13-02-0110 · 4.47 Impact Factor
  • Source
    • "The effect of flavaglines on PHBs-interacting proteins other than C-Raf is also an issue that needs to be examined. Silvestrol is the flavagline that has been the most studied in vivo for its anticancer properties (Alinari et al., 2012; Bordeleau et al., 2008; Cencic et al., 2009; Hwang et al., 2004; Kim et al., 2007; Mi et al., 2006a; Robert et al., 2009; Schatz et al., 2011). However, the development of this compound is severely limited by its sensitivity to P-glycoprotein-mediated multidrug resistance and its suboptimal absorption, distribution, metabolism, and excretion (ADME) characteristics (Gupta et al., 2011; Liu et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prohibitins (PHBs) are scaffold proteins that modulate many signaling pathways controlling cell survival, metabolism, and inflammation. Several drugs that target PHBs have been identified and evaluated for various clinical applications. Preclinical and clinical studies indicate that these PHB ligands may be useful in oncology, cardiology, and neurology, as well as against obesity. This review covers the physiological role of PHBs in health and diseases and current developments concerning PHB ligands.
    Chemistry & biology 03/2013; 20(3):316-31. DOI:10.1016/j.chembiol.2013.02.006 · 6.65 Impact Factor
Show more