Project description:Despite effective strategies, therapy resistance in HER2+ breast cancer remains a challenge. While the Mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Using HER2+ breast cancer parental (P) cell models (AU565, SKBR3, and UACC812), we have established anti-HER2-resistant derivatives made resistant to lapatinib (LR) or lapatinib plus trastuzumab (LTR). We performed RNA-seq on these resistant models and the P cells treated with lapatinib or lapatinib plus trastuzumaba for 24 h. We found that the average expression of the key genes in the MVA pathway, as a surrogate for pathway activity, was dramatically reduced in P cells with short-term treatment. In contrast, expression was restored or further upregulated relative to P cells in all three resistant (LR/LTR) models. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the n-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of resistant cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP), but not by cholesterol. Activated YAP/TAZ and mTORC1 signaling and their downstream target gene product Survivin were inhibited by MVA blockade especially in the LR/LTR models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated S6 levels despite blockade of the MVA. The MVA may provide alternative signaling leading to cell survival and resistance when HER2 is blocked by activating YAP/TAZ-mTORC1-Survivin signaling suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy and warrant further clinical investigation.

2020-04-04 | GSE132055 | GEO

Transient inhibition of JNK pathway improves hematopoietic stem cell engraftment

Project description:We found that transient inhibition of JNK pathway increased short term-HSC frequency in cord blood CD34+ cells by 12.56 folds. Transcriptome analysis shows that inhibition of JNK pathway upregulated HSC-specific and anti-oxidative gene expression, prevented upregulation of cell cycle entry, oxidative phosphorylation and glycolysis related gene expression, and downregulated reactive oxygen species (ROS) active gene expression. Consistently, cell cycle and metabolic analysis show that inhibition of JNK pathway prevented HSC from cell cycle entry, glucose uptake increase and ROS accumulation. Accordingly, transient inhibition of JNK pathway also enhanced long term-HSC recovery during cord blood CD34+ cell collection. Collectively, these findings suggest that transient inhibition of JNK pathway could promote quiescent state of HSCs by preventing cell cycle entry and metabolic activation, thus improving HSC recovery and engraftment ability.

2022-06-29 | GSE165501 | GEO

Targeting JNK Pathway Expands Human Hematopoietic Stem Cells

Project description:The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here we show that culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 6-fold increase in number. These expanded CD34+ cells repopulated recipient mice for 20 weeks and can form secondary engraftment that lasted for more than 21 weeks. Knockdown of c-Jun, a major downstream target in the JNK pathway, significantly promoted the expansion of hematopoietic stem and progenitor cells (HSPCs). Our findings demonstrate a critical role of JNK pathway in regulating HSC expansion, provide new insights into HSC self-renewal mechanism, and may lead to improved clinical application of HSCs.

2019-01-17 | GSE114524 | GEO

Targeting JNK Pathway Expands Human Hematopoietic Stem Cells

Project description:Targeting JNK Pathway Expands Human Hematopoietic Stem Cells

| PRJNA471685 | ENA

IQGAP1 Scaffold-Kinase Interaction Blockade Selectively Targets Ras-MAP Kinase Driven Tumors

Project description:MAPK scaffolds, such as IQGAP1, assemble pathway kinases together to effect signal transmission and disrupting scaffold function therefore offers a potentially orthogonal approach to MAPK cascade inhibition. Consistent with this possibility, we observed an IQGAP1 requirement in Ras-driven tumorigenesis in mouse and human tissue. Delivery of the IQGAP1 WW peptide sequence that mediates Erk1/4 binding, moreover, disrupted IQGAP1-Erk1/2 interactions, abolished Ras/Raf-driven tumorigenesis, bypassed acquired resistance to the B-Raf inhibitor vemurafinib (PLX- 4032), and acts as a systemically deliverable therapeutic to significantly increase lifespan of tumor bearing mice. Scaffold-kinase interaction blockade (SKIB) acts by a mechanism distinct from direct kinase inhibition and represents a strategy to target over-active oncogenic kinase cascades in cancer. Gene expression profiling: Fragmented cRNA was hybridized to the Mouse Gene 1.0 ST Array (Affymetrix). Iqgap1 wild-type and Iqgap1 knockout mouse treated with topical 4OHT for 0 days and 6 days days are compared.

2013-04-01 | E-GEOD-44967 | biostudies-arrayexpress

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