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Argyrin A is a p27 stabilizing drug with potent antiproliferative activity in vivo

ABSTRACT: Reduction in the cellular levels of the cyclin kinase inhibitor p27kip1 are frequently found in many human cancers and correlate directly with patient prognosis. Specifically ubiquitin dependent proteasomal turnover has been shown to cause reduced p27 expression in many human cancers. We recently demonstated that expression of a stabilized version of p27kip1 (p27kip1T187A) in a genetically modified mouse significantly reduced the number of intestinal adenomatous polyps which progressed to invasive carcinomas. Based on this work we set out to identify compounds which lead to a re-expression of p27 in cancer tissues. In this work we identify Argyrin A a compound derived from myxobacterium archangium gephyra as a potent inducer of p27kip1 expression. Argyrin A induces apoptosis in human colon cancer xenografts and tumor vasculature in vivo leading to a profound reduction in tumor size at well tolerated levels. Argyrin A functions are strictly dependent on the expression of p27kip1 as neither tumor cells nor endothelial cells which do not express p27kip1 respond to this compound. Surprisingly the molecular mechanism by which Argyrin A exerts its p27 dependent biological function is through a potent inhibition of the 20S proteasome. Keywords: protasome inhibitor, time course, MCF7 cells, genome wide gene expression response, siRNA

ORGANISM(S): Homo sapiens

PROVIDER: GSE8565 | GEO | 2008/04/29

SECONDARY ACCESSION(S): PRJNA101709

REPOSITORIES: GEO

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siRNA of human MCF7 cells incubated with proteasome inhibitors bortezomib or Argyrin A or proteasome activity and knocked down for proteosomal subunits

Project description:Reduction in the cellular levels of the cyclin kinase inhibitor p27kip1 are frequently found in many human cancers and correlate directly with patient prognosis. Specifically ubiquitin dependent proteasomal turnover has been shown to cause reduced p27 expression in many human cancers. We recently demonstated that expression of a stabilized version of p27kip1 (p27kip1T187A) in a genetically modified mouse significantly reduced the number of intestinal adenomatous polyps which progressed to invasive carcinomas. Based on this work we set out to identify compounds which lead to a re-expression of p27 in cancer tissues. In this work we identify Argyrin A a compound derived from myxobacterium archangium gephyra as a potent inducer of p27kip1 expression. Argyrin A induces apoptosis in human colon cancer xenografts and tumor vasculature in vivo leading to a profound reduction in tumor size at well tolerated levels. Argyrin A functions are strictly dependent on the expression of p27kip1 as neither tumor cells nor endothelial cells which do not express p27kip1 respond to this compound. Surprisingly the molecular mechanism by which Argyrin A exerts its p27 dependent biological function is through a potent inhibition of the 20S proteasome. Experiment Overall Design: MCF7 cells were incubated with proteasome inhibitors bortezomib or Argyrin A or proteasome activity was reduced by treatment with siRNA against proteasomal subunits and gene expression profiles were determined at different timepoints thereafter.

2008-06-16 | E-GEOD-8565 | biostudies-arrayexpress

Expression data from p27WT, p27CK and KO MEFs cells in quiescence

Project description:Low levels of the cell cycle regulator p27Kip1 are associated with a worse outcome in many tumor types. We report here a new regulatory role of p27Kip1 as a transcriptional regulator. In association with transcriptional factors such as ETS and E2F4 and co-repressors like p130, HDACs and mSin3A, p27 binds to promoters of multiple genes leading to their repression. The p27-target genes participate in RNA processing, translation, respiration and cell cycle. Remarkably, p27-target genes are over-expressed in different human tumors in tight association with a poor clinical prognosis. We also observed a clear correlation between low levels of p27 and over-expression of p27-target genes in tumors. Overall, our findings indicate new tumor suppressor roles of p271 as a transcriptional regulator of genes relevant for oncogenesis.

2011-12-01 | GSE27672 | GEO

Expression data from p27WT, p27CK and KO MEFs cells in quiescence

2011-12-01 | E-GEOD-27672 | biostudies-arrayexpress

Expression data from p27delta51 MEFs cells in quiescence

Project description:Low levels of the cell cycle regulator p27Kip1 are associated with a worse outcome in many tumor types. We report here a new regulatory role of p27Kip1 as a transcriptional regulator. In association with transcriptional repressors such as p130, E2F4 and HDACs, p27 binds to promoters of multiple genes leading to their repression. The p27Kip1-target genes participate in RNA processing, translation, respiration and cell cycle. Remarkably, p27Kip1-target genes are over-expressed in different human tumors in tight association with a poor clinical prognosis. We also observed a clear correlation between low levels of p27Kip1 and over-expression of p27Kip1-target genes in tumors. Overall, our findings indicate new tumor suppressor roles of p27Kip1 as a transcriptional regulator of genes relevant for oncogenesis.

2011-12-01 | GSE20064 | GEO

Expression data from p27delta51 MEFs cells in quiescence

Project description:Low levels of the cell cycle regulator p27Kip1 are associated with a worse outcome in many tumor types. We report here a new regulatory role of p27Kip1 as a transcriptional regulator. In association with transcriptional repressors such as p130, E2F4 and HDACs, p27 binds to promoters of multiple genes leading to their repression. The p27Kip1-target genes participate in RNA processing, translation, respiration and cell cycle. Remarkably, p27Kip1-target genes are over-expressed in different human tumors in tight association with a poor clinical prognosis. We also observed a clear correlation between low levels of p27Kip1 and over-expression of p27Kip1-target genes in tumors. Overall, our findings indicate new tumor suppressor roles of p27Kip1 as a transcriptional regulator of genes relevant for oncogenesis. Samples from MEFs p27delta51 and p27WT cells used as control were analyzed

2011-12-01 | E-GEOD-20064 | biostudies-arrayexpress

Contact inhibition controls miR-223 stabilization via p27kip1 expression

Project description:The control of cell cycle progression mostly relays on the concerted activity of cyclins, CDKs and CDKs inhibitor. Recent data demonstrated that microRNAs, by regulating the expression of these proteins, contribute to the control of cell cycle progression. Here we provide evidences that the CDK inhibitor p27Kip1 directly regulates microRNAs stability thereby influencing cell cycle exit following contact inhibition. By the use of wild type and p27 knock-out cells we uncovered several microRNAs whose expression is linked to the cell cycle exit in a p27-dependent manner. By studying one of this microRNA, miR-223, we provide evidence that p27 is an RNA binding protein able to bind miR-223 to stabilize its expression. High miR-223 levels participate in the control of cell proliferation. Overall, we identify a previously completely unknown and conserved function of p27Kip1 that contributes to the proper regulation of cell cycle progression impinging on microRNA expression.

2015-12-31 | E-GEOD-45538 | biostudies-arrayexpress

Contact inhibition controls miR-223 stabilization via p27kip1 expression

2015-12-31 | GSE45538 | GEO

Genetic characterization of p27Kip1 and stathmin role in controlling cell proliferation in vivo

Project description:The CDK inhibitor p27Kip1 is a critical regulator of cell cycle progression, but the mechanisms by which p27Kip1 controls cell proliferation in vivo are still not fully elucidated. We recently demonstrated that the microtubule destabilizing protein stathmin is a relevant p27Kip1binding partner involved in the regulation of cell motility. To get more insights into the in vivo significance of this interaction, we generated p27Kip1 and stathmin double knock out (DKO) mice. Interestingly, thorough characterization of DKO mice demonstrated that most of the phenotypes of p27Kip1 null mice linked to the hyperproliferative behavior, such as the increased body and organ weights, the outgrowth of the retina basal layer and the development of pituitary adenomas, were reverted by co-ablation of stathmin. In vivo analyses showed a reduced proliferation rate in DKO compared to p27kip1 null mice, linked, at molecular level, to decreased kinase activity of CDK4/6, rather than of CDK1 and CDK2. Gene expression profile analyses of mouse thymuses confirmed the phenotypes observed in vivo, demonstrating that DKO clustered with WT and not with p27KO thymuses. Taken together, the results demonstrate that stathmin cooperates with p27Kip1 to control the early phase of G1 to S phase transition and strongly suggest that this function has particular relevance in the contest of tumor progression. Four-conditions experiment (four different mouse genotypes), 6 biological replicates of wild type mouse thymus, 6 biological replicates of p27 knock-out mouse thymus, 6 biological replicates of stathmin knock-out mouse thymus, 6 biological replicates of double knock-out (p27 and stathmin) mouse thymus. Reference design: pool of RNAs derived from mouse fibroblasts of all the genotypes.Reference design;

2015-04-01 | E-GEOD-60078 | biostudies-arrayexpress

Functional determinants of sensitivity to CDK4/6 inhibition or cell-cycle plasticity

Project description:Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors have emerged as a major obstacle that hinders their utility beyond ER+ breast cancer. Palbociclib-sensitive ER+ breast cancer models and pancreatic ductal adenocarcinoma (PDAC) models were employed to identify functional determinants of response. In all models tested the activation of RB and inhibition of CDK2 activity emerged as determinants of sensitivity. While depleting CDK4 and 6 was sufficient to limit proliferation in specific resistance setting, RB loss renders cells completely CDK4/6 independent. The main down-stream target in this context is the activation status of CDK2 which is suppressed with CDK4/6 inhibition in an RB-dependent fashion. The P27KIP1 protein levels are associated with plasticity/rigidity of the cell cycle and correlates with sensitivity to CDK4/6 inhibiion. Exogenous overexpression and pharmacological induction of P27KIP1 by targeting the MEK/ERK pathway enhances the cytostatic effect of palbociclib. Similar to cell-culture data, in vivo experiments revealed that combination treatment of palbociclib and trametinib in mice bearing PDAC PDXs elicited a robust anti-proliferative effect with a corresponding increase in p27 expression. Mice bearing MCF7 xenografts displayed a durable response in the presence of palbociclib; however, over the course of treatment few cells begin to evade the negative cell-cycle regulation. Based on multispectral staining, the MCF7 tumor cells that underwent RB inactivation in the presence of palbociclib harbored low p27 expression. Finally, we demonstrate that the cell-cycle plasticity that enables tumor models to evade the palbociclib mediated RB activation could be potently targeted using a clinically applicable CDK2 inhibitor.

2020-06-30 | GSE146788 | GEO

BCR-ABL1 promotes leukemia by converting p27 into a cytoplasmic oncoprotein

Project description:Coordinated BCR-ABL1 kinase-dependent and -independent mechanisms convert p27 from a nuclear tumor suppressor to a cytoplasmic oncogene. Persistence of oncogenic p27 functions despite effective inhibition of BCR-ABL1 may contribute to resistance to tyrosine kinase inhibitors. BCR-ABL1 induced p27 versus knockout, controlling with Empty vector p27 versus knock out

2014-10-08 | E-GEOD-59168 | biostudies-arrayexpress

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