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PDK1 Signaling Towards PLK1-Myc Activation Confers Oncogenic Transformation and Tumor Initiating Cell Activation and Resistance to mTOR-targeted Therapy.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30669 | GEO | 2013/07/31

SECONDARY ACCESSION(S): PRJNA144447

REPOSITORIES: GEO

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PDK1 Signaling Towards PLK1-Myc Activation Confers Oncogenic Transformation and Tumor Initiating Cell Activation and Resistance to mTOR-targeted Therapy.

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

2013-07-31 | E-GEOD-30669 | biostudies-arrayexpress

Pharmacological target dysfunction cell cycle pathways induce vulnerabilities of chemotherapy in colorectal cancer

Project description:Dysfunction of cell cycle genes can lead to mitosis disruption and chromosomal instability (CIN), which is blamed for poor prognosis in colorectal cancer (CRC) patients, no matter with chemotherapy or not. Discovery therapeutic targets to abnormal cell cycle pathways in CRC may help to improve current therapy. By genome-widely profiling of differential expressed genes in 54 pairs of human colorectal tumor with matched normal mucosa, we found a functional enrichment in PLK1 signaling. Tumors with enriched PLK1 signaling are accompanied with dysfunction pathways related to cell cycle. Total PLK1 and phosphorylated PLK1 protein expression are associated with tumor recurrence and poor overall survival in a cohort of CRC patients. Combining PLK1 inhibitor with oxaliplatin shows a synergize effect to suppress the growth of CRC cell lines, xenograft tumors, preclinical patient-derived organoid and patient-derived xenograft tumors. RNA-seq data reveals that the cell cycle pathways were activated in oxaliplatin group but inhibited after PLK1 inhibitor treatment. CDC7 may be a key downstream effector of PLK1 induced oxaliplatin resistance and can be druggable. Further investigation showed that PLK1 inhibitor suppress the CDC7 expression via c-MYC transcriptional control. A strong positive correlation between PLK1 and CDC7 has been further confirmed in patients. Strikingly, functional studies confirm that combining CDC7 inhibitor with oxaliplatin can recapitulate the synergize effect in various CRC models, highlighting pharmacological target PLK1-MYC-CDC7 signaling as a potential therapeutic strategy for oxaliplatin based chemotherapy.

2023-10-24 | GSE160089 | GEO

Diffusible factors released from human prostate carcinoma cells restrained cancer stem cells from contributing to tumor progression

Project description:The growth and progression of many cancers is thought to be driven by small subpopulations of cancer stem cells (CSC). Long-term cultures of CSC have been established to develop therapeutic strategies aimed at eradicating these tumorigenic cells. To evaluate the contribution of CSC to the progression of prostate cancer we isolated a CD44+CD24- tumor cell population from the DU145 cell line, derived from a brain metastasis of human prostate carcinoma, and established their CSC properties. The behaviour of selected CSC was then investigated with respect to the bulk DU145 cells. Interestingly, CSC were able to generate very aggressive tumors in immunodeficient mice, but this capacity was interfered by the presence of differentiated DU145 cells, resulting in the growth of scarcely aggressive tumors. To understand the influence of DU145 cells on CSC we performed co-culture experiments, demonstrating that signals released from differentiated tumor cells interfered with CSC acquisition of an aggressive phenotype. Our findings highlight that the fate of prostate CSC can be controlled by microenvironmental signals that restrain CSC from contributing to prostate cancer progression. Finally, we identified several molecules possibly involved in this cell-to-cell signaling, hypothesizing their potential value as novel prognostic markers or therapeutic targets. To investigate the cellular response involved in tumorigenesis both at the level of gene expression and at the pre-mRNA splicing level we performed a whole genome microarray analysis of two paradigmatic experimental conditions, DU145 cells and their selected CSC.

2013-03-01 | E-GEOD-28313 | biostudies-arrayexpress

STK38 is a Key Regulator of MYC Transcriptional Activity in Human B lymphoma cells

Project description:Post-translational regulation of the MYC Transcription Factor (TF), including its phosphorylation and ubiquitination, plays an important role in determining cell proliferation and apoptosis and has been implicated in tumorigenesis. Using a computational systems biology approach, followed by biochemical and functional validation, we have characterized the role of the STK38 kinase, an NDR family serine-threonine kinase, as a key modulator of MYC transcriptional activity in human B cells, affecting MYC protein stability in a signal-dependent fashion. Specifically, we show that in human B lymphoma ST486 cells STK38 is a key mediator of BCR pathway signaling, affecting MYC protein turnover and its phosphorylation at Ser62 in kinase-activity-dependent manner. STK38 inactivation abrogates apoptosis following BCR activation while its silencing mediates MYC protein degradation via canonical proteolytic pathways. This suggests that STK38 could provide an effective therapeutic target in MYC-dependent malignancies. ST486 human Burkitt's lymphoma cells were transduced with STK38 shRNA lentiviral vectors.

2012-01-06 | E-GEOD-20229 | biostudies-arrayexpress

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [ID8 and ID8-IP / KMF cells]

Project description:Gene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-b-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/b-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.

2019-07-01 | GSE129097 | GEO

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [KMF parental, KMF clone KT13 (FAK-/-), KT13 + GFP-FAK, KT13 + GFP-FAK R454, and KT13 + deltaGSK beta-catenin]

2019-07-01 | GSE129098 | GEO

CEP55 is a determinant of cell fate during perturbed mitosis in breast cancer

Project description:The centrosomal protein, CEP55 is a key regulator of cytokinesis and its overexpression is linked to genomic instability, a hallmark of cancer. However, the mechanism by which it mediates genomic instability remains elusive. Here, we showed that CEP55 overexpression/knockdown impacts survival of aneuploid cells. Loss of CEP55 sensitizes breast cancer cells to anti-mitotic agents through premature CDK1/Cyclin B activation and CDK1-Caspase-dependent mitotic cell death. Further, we showed that CEP55 is a downstream effector of the MEK1/2-MYC axis. Blocking MEK1/2-PLK1 signaling therefore reduced outgrowth of basal-like syngeneic and human breast tumors in in-vivo models. In conclusion, high CEP55 levels dictate cell fate during perturbed mitosis. Forced mitotic cell death by blocking MEK1/2-PLK1 represents a potential therapeutic strategy for MYC-CEP55-dependent basal-like, triple-negative breast cancers.

2018-07-14 | GSE117058 | GEO

MITOCHONDRIAL Akt REGULATION OF HYPOXIC METABOLIC REPROGRAMMING

Project description:Hypoxia is a driver of aggressive tumor behavior, but the mechanisms are not completely understood. In a global phosphoproteomics screen, we now demonstrate that hypoxia induces the recruitment of Akt2 to tumor mitochondria, and Akt phosphorylation of pyruvate dehydrogenase kinase (PDK1) on Thr346. In turn, Akt-phosphorylated PDK1 shuts off oxidative phosphorylation via phosphorylation of the pyruvate dehydrogenase complex, and reprograms tumor metabolism towards glycolysis. Akt-phosphorylation of PDK1 is required to prevent autophagy, maintain cell viability and support tumor cell proliferation in hypoxia, in vivo. Therefore, mitochondrial Akt is a pathophysiologic switch for tumor adaptation in hypoxia.

2016-04-20 | MSV000079671 | MassIVE

Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability

Project description:Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free dNTPs. How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins are central regulators that coordinate nucleotide synthesis and ROS generation to drive the development of numerous human cancers. We herein performed a CRISPR-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven metabolic dependency. Mechanistically, MYC orchestrated the balance of two metabolic pathways that act in parallel, the NOX4-ROS pathway and the PLK1-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as the first-in-class degrader that potently and selectively depletes NUDT1 in vivo. Administration of LC-1-40 disrupted MYC-controlled metabolic homeostasis, resulting in excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.

2023-12-27 | PXD043444 | Pride

AKT but not MYC promotes reactive oxygen species-mediated cell death in oxidative culture

Project description:In addition to driving tumorigenesis, oncogenes can create metabolic vulnerabilities in cancer cells. Here, we tested how the oncogenes AKT and MYC affect the ability to shift between respiration and glycolysis. Using immortalized mammary epithelial cellsMCF10A, we discovered constitutively active AKT but not MYC induced cell death in galactose culture, where cells must rely on oxidative phosphorylation for energy generation. However, the negative effects of AKT were short-lived, and AKT-expressing cells recommenced growth after ~15 days in galactose culture. To identify the mechanisms regulating AKT-mediated cell death, we first used metabolomics and found that AKT cells dying in galactose culture exhibited upregulated glutathione metabolism. Next, using shotgun proteomics, we discovered AKT cells dying in galactose upregulated proteins related to nonsense-mediated mRNA decay (NMD), a known response to oxidative stress. We therefore measured levels of reactive oxygen species (ROS) and discovered galactose culture induced ROS only in cells expressing AKT. Additionally, we found thatdiscovered the ROS scavenger catalase rescued AKT-expressing cells from galactose culture-induced cell death. We then demonstrated that breast cancer cell lines with constitutively active AKT signaling also exhibited cell death in galactose culture and rescue by catalase. Together, our results demonstrate that AKT but not MYC induces a metabolic vulnerability in cancer cells, namely the that restricted flexibility to use oxidative phosphorylation.

2020-03-19 | PXD015122 | Pride

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