Translational control of cell fate: From integration of environmental signals to breaching anticancer defense

Bitterman, Peter B.; Polunovsky, Vitaly A.

doi:10.4161/cc.11.6.19610

Cited by 21 publications

(23 citation statements)

References 124 publications

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“…These findings lend more credence to the observation of numerous other investigators that mRNA translation is a major regulatory checkpoint in cancer cells that is a legitimate target for cancer therapy 25, 26 . Furthermore, in complex tumors with redundant signaling pathways, cap-dependent translation is an important downstream effector of these signaling pathways affecting cell survival and proliferation.…”

Section: Discussionsupporting

confidence: 70%

Resistance to EGFR-TKI Can Be Mediated through Multiple Signaling Pathways Converging upon Cap-Dependent Translation in EGFR-Wild Type NSCLC

Patel

Jay-Dixon

Sadiq

et al. 2013

Journal of Thoracic Oncology

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INTRODUCTION For the majority of patients with non-small cell lung cancer, response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) is suboptimal. In models of acquired resistance to EGFR-TKI, activation of Akt phosphorylation is frequently observed. Since Akt activation results in downstream initiation of cap-dependent protein translation, we hypothesized that a strategy of targeting cap-dependent translation in combination with erlotinib might enhance therapy. METHODS NSCLC cells that are wild-type for Egfr were assayed for sensitivity to erlotinib. Serum-starved NSCLC cells were assayed for EGFR signaling and downstream pathway activation by immunoblot after stimulation with EGF. EGFR signaling and signaling mediators of cap-dependent translation were assayed by immunoblot under serum replete conditions 24 hours after treatment with erlotinib. Finally, combination treatment with erlotinib and 2 different cap-dependent translation inhibitors were done to assess the effect on cell viability. RESULTS EGFR signaling is coupled to activation of cap-dependent translation in EGFR wild-type cells. Erlotinib inhibits EGFR phosphorylation in EGFR-TKI resistant cells, however, results in activation of downstream signaling molecules including Akt and ERK1/2 resulting in maintenance of eIF4F activation. eIF4F cap-complex formation is maintained in erlotinib resistant cells, but not in erlotinib sensitive cells. Finally, using an antisense oligonucleotide against eIF4E and a small-molecule inhibitor to disrupt eIF4F formation, we show that cap-dependent translation inhibition can enhance sensitivity to erlotinib. Conclusions The results of these studies support further clinical development of translation inhibitors for treatment of NSCLC in combination with erlotinib.

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Section: Discussionsupporting

confidence: 70%

Resistance to EGFR-TKI Can Be Mediated through Multiple Signaling Pathways Converging upon Cap-Dependent Translation in EGFR-Wild Type NSCLC

Patel

Jay-Dixon

Sadiq

et al. 2013

Journal of Thoracic Oncology

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“…Such individuals would represent a potentially identifiable high-risk group for PABC or other malignancies that occur in tissues with actively proliferating stem/progenitor cell populations such as the gastrointestinal tract and bone marrow. Our findings imply that therapeutic interventions to normalize aberrant eIF4E function might not only be promising for advanced cancers (3, 43–45), but might also be productively studied for cancer prevention or interception of the neoplastic process at its early stages.…”

Section: Discussionmentioning

confidence: 83%

“…Dysregulation of translation initiation is frequent in malignancy (1–3). The cap-binding protein eIF4E is a rate-limiting component of the translation initiation complex eIF4F (4).…”

Section: Introductionmentioning

confidence: 99%

eIF4E Threshold Levels Differ in Governing Normal and Neoplastic Expansion of Mammary Stem and Luminal Progenitor Cells

et al. 2015

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Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biological outputs remains unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased cell self-renewal, triggered DNA replication stress, and induced formation of pre-malignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H-RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biological output in lactating mammary glands, and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its pro-neoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer.

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“…Indeed, signals triggered by different stimuli often travel through shared network segments that operate as hubs, before reaching the effectors of the cellular response (Bitterman and Polunovsky, 2012; Gao and Chen, 2010). Hubs’ inherent pleiotropy means that their inhibition may have broad and likely undesired effects (Karin, 2008; Berger and Iyengar, 2010; Force et al, 2007; Oda and Kitano, 2006; Zhang et al, 2008) – this is a major obstacle for the efficacy of drugs targeting prominent signaling hubs such as p53, MAPK or IKK.…”

Section: Introductionmentioning

confidence: 99%

The Dynamics of Signaling as a Pharmacological Target

Behar

Barken

Werner

et al. 2013

Cell

126

124

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Highly networked signaling hubs are often associated with disease, but targeting them pharmacologically has largely been unsuccessful in the clinic because of their functional pleiotropy. Motivated by the hypothesis that a dynamical signaling code confers functional specificity, we investigated whether dynamical features may be targeted pharmacologically to achieve therapeutic specificity. With a virtual screen we identified combinations of signaling hub topologies and dynamic signal profiles that are amenable to selective inhibition. Mathematical analysis revealed principles that may guide stimulus-specific inhibition of signaling hubs, even in the absence of detailed mathematical models. Using the NFκB signaling module as a test bed, we identified perturbations that selectively affect the response to cytokines or pathogen components. Together, our results demonstrate that the dynamics of signaling may serve as a pharmacological target, and we reveal principles that delineate the opportunities and constraints of developing stimulus-specific therapeutic agents aimed at pleiotropic signaling hubs.

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Translational control of cell fate: From integration of environmental signals to breaching anticancer defense

Cited by 21 publications

References 124 publications

Resistance to EGFR-TKI Can Be Mediated through Multiple Signaling Pathways Converging upon Cap-Dependent Translation in EGFR-Wild Type NSCLC

Resistance to EGFR-TKI Can Be Mediated through Multiple Signaling Pathways Converging upon Cap-Dependent Translation in EGFR-Wild Type NSCLC

eIF4E Threshold Levels Differ in Governing Normal and Neoplastic Expansion of Mammary Stem and Luminal Progenitor Cells

The Dynamics of Signaling as a Pharmacological Target

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