Dataset Information

Silencing c-Myc translation as a therapeutic strategy through targeting PI3K? and CK1? in hematological malignancies.

ABSTRACT: Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K ? isoform inhibitor TGR-1202, but not the approved PI3K? inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilzomib in lymphoma, leukemia, and myeloma cell lines and primary lymphoma and leukemia cells. TGR-1202 and carfilzomib (TC) synergistically inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), leading to suppression of c-Myc translation and silencing of c-Myc-dependent transcription. The synergistic cytotoxicity of TC was rescued by overexpression of eIF4E or c-Myc. TGR-1202, but not other PI3K? inhibitors, inhibited casein kinase-1 ? (CK1?). Targeting CK1? using a selective chemical inhibitor or short hairpin RNA complements the effects of idelalisib, as a single agent or in combination with carfilzomib, in repressing phosphorylation of 4E-BP1 and the protein level of c-Myc. These results suggest that TGR-1202 is a dual PI3K?/CK1? inhibitor, which may in part explain the clinical activity of TGR-1202 in aggressive lymphoma not found with idelalisib. Targeting CK1? should become an integral part of therapeutic strategies targeting translation of oncogenes such as c-Myc.

SUBMITTER: Deng C

PROVIDER: S-EPMC5216267 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies.

Deng Changchun C Lipstein Mark R MR Scotto Luigi L Jirau Serrano Xavier O XO Mangone Michael A MA Li Shirong S Vendome Jeremie J Hao Yun Y Xu Xiaoming X Deng Shi-Xian SX Realubit Ronald B RB Tatonetti Nicholas P NP Karan Charles C Lentzsch Suzanne S Fruman David A DA Honig Barry B Landry Donald W DW O'Connor Owen A OA

Blood 20161026 1

Phosphoinositide 3-kinase (PI3K) and the proteasome pathway are both involved in activating the mechanistic target of rapamycin (mTOR). Because mTOR signaling is required for initiation of messenger RNA translation, we hypothesized that cotargeting the PI3K and proteasome pathways might synergistically inhibit translation of c-Myc. We found that a novel PI3K δ isoform inhibitor TGR-1202, but not the approved PI3Kδ inhibitor idelalisib, was highly synergistic with the proteasome inhibitor carfilz ...[more]

PMID: 27784673

Similar Datasets

Project description:The human genome project revealed the existence of many thousands of long non-coding RNAs (lncRNAs). These transcripts that are over 200 nucleotides long were soon recognized for their importance in regulating gene expression. However, their poor conservation among species and their still controversial annotation has limited their study to some extent. Moreover, a generally lower expression of lncRNAs as compared to protein coding genes and their enigmatic biochemical mechanisms have impeded progress in the understanding of their biological roles. It is, however, known that lncRNAs engage in various kinds of interactions and can form complexes with other RNAs, with genomic DNA or proteins rendering their functional regulatory network quite complex. It has emerged from recent studies that lncRNAs exert important roles in gene expression that affect many cellular processes underlying development, cellular differentiation, but also the pathogenesis of blood cancers like leukemia and lymphoma. A number of lncRNAs have been found to be regulated by several well-known transcription factors including Myelocytomatosis viral oncogene homolog (MYC). The c-MYC gene is known to be one of the most frequently deregulated oncogenes and a driver for many human cancers. The c-MYC gene is very frequently activated by chromosomal translocations in hematopoietic cancers most prominently in B- or T-cell lymphoma or leukemia and much is already known about its role as a DNA binding transcriptional regulator. Although the understanding of MYC's regulatory role controlling lncRNA expression and how MYC itself is controlled by lncRNA in blood cancers is still at the beginning, an intriguing picture emerges indicating that c-MYC may execute part of its oncogenic function through lncRNAs. Several studies have identified lncRNAs regulating c-MYC expression and c-MYC regulated lncRNAs in different blood cancers and have unveiled new mechanisms how these RNA molecules act. In this review, we give an overview of lncRNAs that have been recognized as critical in the context of activated c-MYC in leukemia and lymphoma, describe their mechanism of action and their effect on transcriptional reprogramming in cancer cells. Finally, we discuss possible ways how an interference with their molecular function could be exploited for new cancer therapies.

Dataset Information

Silencing c-Myc translation as a therapeutic strategy through targeting PI3K? and CK1? in hematological malignancies.

Publications

Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets