title: Accumulation of dephosphorylated 4EBP after mTOR inhibition with rapamycin is sufficient to disrupt paracrine transformation by the KSHV vGPCR oncogene.
abstract: Dysregulation of the PI3K/Akt/mTOR pathway is one of the most frequent events in human cancer. However, the clinical benefits of PI3K/Akt/mTOR inhibitors have not yet achieved their predicted potential in many of the most prevalent human cancers. Of interest, treatment of Kaposi's sarcoma (KS) patients with rapamycin provided the first evidence of the antineoplastic activity of mTOR inhibitors in humans, becoming the standard of care for KS arising in renal transplant patients. Thus, the study of KS may provide a unique opportunity to dissect the contribution of specific mTOR downstream targets to cancer development. The KS-associated herpesvirus (KSHV) is the etiological agent for KS, and the KSHV-encoded oncogene viral-G protein-coupled receptor (vGPCR) promotes the potent activation of the PI3K-Akt-mTOR pathway by both direct and paracrine mechanisms. We focused on a direct target of mTOR, EIF4EBP1/2/3 (4EBP), which inhibits the translation of eukaryotic initiation factor 4E (eiF4E)-bound mRNAs. 4EBP phosphorylation by mTOR relieves its inhibitory activity, hence resulting in increased eiF4E-dependent mRNA translation. We developed a paracrine transformation model, recapitulating the cellular composition of KS lesions, in which vGPCR-expressing cells promote the rapid proliferation of endothelial cells, thus expressing KSHV-latent genes by the release of growth factors. Using this model, we show here that the accumulation of dephosphorylated 4EBP in response to rapamycin or by the expression of an mTOR-insensitive mutant of 4EBP1 is sufficient to disrupt the eiF4E function downstream of mTOR to a similar extent than the mTOR catalytic inhibitor Torin2 and to halt KS development. We also provide evidence that eiF4E contributes to paracrine neoplastic, signaling through the release of pro-angiogenic factors that are acting on endothelial cells, expressing KSHV-latent genes. These findings may provide a preclinical platform and the rationale for the development of novel mTOR, inhibiting agents that may selectively disrupt the mTOR-4EBP interaction for the treatment of KS and other tumor lesions, exhibiting hyperactive mTOR pathway function.
authors.affiliation: Oral and Pharyngeal Cancer Branch; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Martin
authors.affiliation: Oral and Pharyngeal Cancer Branch; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Nguyen
authors.affiliation: Oral and Pharyngeal Cancer Branch; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Molinolo
authors.affiliation: Oral and Pharyngeal Cancer Branch; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002472:Cell Transformation, Viral; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D019288:Herpesvirus 8, Human; D006801:Humans; D009857:Oncogenes; D019899:Paracrine Communication; D010750:Phosphoproteins / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000473:pathology* / Q000821:virology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C104151:EIF4EBP2 protein, human; C112661:EIF4EBP3 protein, human; D039642:Eukaryotic Initiation Factors; C115448:G protein-coupled receptor, Human herpesvirus 8; D010750:Phosphoproteins; D019707:Receptors, Chemokine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus