MTOR signaling pathway and targeting c-myc
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA872020 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21160486.fastq.gz | Fastqsanger.gz | |||
| SRR21160487.fastq.gz | Fastqsanger.gz | |||
| SRR21160488.fastq.gz | Fastqsanger.gz | |||
| SRR21160489.fastq.gz | Fastqsanger.gz | |||
| SRR21160490.fastq.gz | Fastqsanger.gz |
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Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance. Gene expression profiling of Human Embryonic Kidney Cells (HEK-TERV) under different conditions: PMN, PDK1, MYC and E545K
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Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance.
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Project description:mTOR is an important anti-cancer target that integrates diverse signals to control protein synthesis and cell growth. Numerous studies by using mTOR inhibitors and/or gene deletion of mTOR negative regulators have implicated mTOR targeting in suppressing gene expression and cell proliferation. However, we found that gene targeting of mTOR in mouse hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to mTOR loss, mTOR-/- HSCs increase chromatin access and activate global gene expression, in contrast to short-term inhibition by mTOR inhibitors. Such genomic changes are due to a compensatory activation of a MAPK/Mnk/eIF4E signaling pathway that enhances the translation of RNA pol-II and consequent c-myc expression. This adaptive mechanism can also be adopted by leukemia stem cells undergone long-term mTOR inhibitor treatment to confer resistant to mTOR targeting. Our studies provide new insights and a foregone strategy for overcoming drug resistance in mTOR targeted therapy.
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