Targeted inhibition of cooperative mutation- and therapy-induced AKT activation in AML effectively enhances response to chemotherapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA631272 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-11-10 | GSE150161 | GEO
Project description:Cancer stem cells are believed to play a crucial role in cancer recurrence due to their resistance to conventional chemotherapy and capacity for self-renewal. Recent studies have reported that salinomycin, a livestock antibiotic, selectively targets breast cancer stem cells 100-fold more effectively than paclitaxel. In our study we sought to determine the effects of salinomycin on head and neck squamous cell carcinoma (HNSCC) stem cells. We show that salinomycin is able to decrease cell viability and induce apoptosis. In combination with the chemotherapeutic agents cisplatin and paclitaxel, salinomycin synergistically killed HNSCC cancer stem cells more effectively than either drug alone. Furthermore, we observed that salinomycin decreases stem cell properties as shown by a significant reduction in sphere formation and a decrease of both CD44 and BMI-1. Contrary to expectations, salinomycin caused an induction of EMT as shown by an increase in Snail and Vimentin, and a decrease in E-cadherin expression. Even though EMT was induced, salinomycin caused a decrease in invasion through a membrane. In search of a possible mechanism, the effects on the Akt pathway were explored. Interestingly, salinomycin also induced phosphorylation of Akt. Activation of EMT and Akt are both tightly associated with an increase in stemness, which brings to question the relationship between CSCs and these two fundamental pathways. Taken together, our findings indicate that salinomycin shows promise as a novel treatment for HNSCC despite an activation of EMT and Akt. MicroRNA obtained from JLO-1 cells treated for 48 hours in varying doses of salinomycin. Changes in microRNA expression are analyzed by normalizing expression values with the control sample.
2013-12-31 | E-GEOD-33196 | biostudies-arrayexpress
Project description:FOXM1 and AKT are crucial pro-oncogenic regulators of cancer therapy resistance. Due to reciprocal regulatory links they establish a positive feedback autoregulation loop in AML cells. Disruption of this loop via inhibition of either FOXM1 or AKT results in similar gene expression changes, drastic upregulation of HOXA genes and sensitization of AML cells to cytarabine and venetoclax treatment.
2021-08-18 | GSE172189 | GEO
Project description:Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs.
| S-EPMC4317339 | biostudies-literature
Project description:Small-molecule inhibitors of AKT signaling are being in evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with sub-therapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multi-scale, molecular snapshot of this âAKTlowâ cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously up-regulate a host of other proteins and metabolites post-transcriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication. Profiles of MCF7 and HCT116 Akti-1/2 treated cells and MCF7 and HCT116 vehicle (i.e. DMSO) treated cells were generated, each in duplicate, using RNA-Seq.
2015-12-09 | E-GEOD-71900 | biostudies-arrayexpress
Project description:Small-molecule inhibitors of AKT signaling are being in evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with sub-therapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multi-scale, molecular snapshot of this âAKTlowâ cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously up-regulate a host of other proteins and metabolites post-transcriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication. Profiles of MCF7 and HCT116 Akti-1/2 treated cells and MCF7 and HCT116 vehicle (i.e. DMSO) treated cells were generated, each in duplicate, using GRO-Seq.
2015-12-09 | E-GEOD-71898 | biostudies-arrayexpress
Project description:This phase II clinical trial studies how well Akt inhibitor MK2206 works in treating patients with relapsed lymphoma. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
| 2099453 | ecrin-mdr-crc
Project description:Cancer stem cells are believed to play a crucial role in cancer recurrence due to their resistance to conventional chemotherapy and capacity for self-renewal. Recent studies have reported that salinomycin, a livestock antibiotic, selectively targets breast cancer stem cells 100-fold more effectively than paclitaxel. In our study we sought to determine the effects of salinomycin on head and neck squamous cell carcinoma (HNSCC) stem cells. We show that salinomycin is able to decrease cell viability and induce apoptosis. In combination with the chemotherapeutic agents cisplatin and paclitaxel, salinomycin synergistically killed HNSCC cancer stem cells more effectively than either drug alone. Furthermore, we observed that salinomycin decreases stem cell properties as shown by a significant reduction in sphere formation and a decrease of both CD44 and BMI-1. Contrary to expectations, salinomycin caused an induction of EMT as shown by an increase in Snail and Vimentin, and a decrease in E-cadherin expression. Even though EMT was induced, salinomycin caused a decrease in invasion through a membrane. In search of a possible mechanism, the effects on the Akt pathway were explored. Interestingly, salinomycin also induced phosphorylation of Akt. Activation of EMT and Akt are both tightly associated with an increase in stemness, which brings to question the relationship between CSCs and these two fundamental pathways. Taken together, our findings indicate that salinomycin shows promise as a novel treatment for HNSCC despite an activation of EMT and Akt.
2013-12-31 | GSE33196 | GEO
Project description:Chemoresistance is the leading cause of acute myeloid leukemia (AML)-related deaths, and elucidation of the mechanisms of AML chemoresistance is necessary to effectively target this process. Here, we performed genome wide CRISPR-Cas9 screening to identify key molecules regulating AML chemoresistance.
2023-06-30 | GSE235688 | GEO
Project description:Small-molecule inhibitors of AKT signaling are being in evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with sub-therapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multi-scale, molecular snapshot of this â??AKTlowâ?? cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously up-regulate a host of other proteins and metabolites post-transcriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication. Secreted protein profiles of MCF7 and HCT116 Akti-1/2 treated cells and MCF7 and HCT116 vehicle (i.e. DMSO) treated cells were generated using antibody arrays.
2015-12-09 | E-GEOD-71892 | biostudies-arrayexpress