ABSTRACT: Transcriptional profiles of multiple cell and perturbation types: 23 cells are treated with 311 chemical perturbagens and CRISPR reagents. The expression level for 978 representative genes is measured.
Project description:Transcriptional profiles of multiple cell and perturbation types: cells are treated with chemical and genetic perturbations. The expression level for 978 representative genes is measured.
Project description:Transcriptional profiles of multiple cell and perturbation types: cells are treated with chemical perturbagens and CRISPR reagents. The expression level for 978 representative genes is measured.
Project description:Transcriptional profiles of multiple cells treated with small molecule perturbagens: The expression level is measured for 978 representative genes in 15 cell lines treated with 241 small molecules.
Project description:Transcriptional profiles of cultured human cancer cell lines treated with small molecules: Expression of 978 representative genes is measured in 39 cell lines perturbed by 13 thousands of small molecules.
Project description:Transcriptional profiles of cultured human breast and prostate cancer cell lines treated with small molecules: 6 cancer cell lines are treated with 6 small molecules, as a part of the LINCS Trans-Center Project. The expression level for 978 representative genes is measured.
Project description:Transcriptional profiles of cultured human breast cancer cell lines treated with small molecules: 5 cell lines are treated with 109 small molecules and the expression of 978 representative genes is measured, as a part of the LINCS Joint Project.
Project description:High-throughput phenotype-based screening of large libraries of novel compounds without known targets can identify small molecules that elicit a desired cellular response, but additional approaches are required to find and characterize their targets and mechanisms of action. Here we show that a compound termed lung cancer screen 3 (LCS3), previously selected for its ability to impair the growth of human lung adenocarcinoma (LUAD) cell lines, but not normal lung cells, induces oxidative stress and activates the NRF2 signaling pathway by generating reactive oxygen species (ROS) in sensitive LUAD cell lines. To identify the target that mediates this effect, we applied thermal proteome profiling (TPP) and uncovered the disulfide reductases GSR and TXNRD1 as LCS3 targets. Through enzymatic assays using purified protein, we confirmed that LCS3 inhibits disulfide reductase activity through a reversible, uncompetitive mechanism. Further, we demonstrate that LCS3-sensitive LUAD cells are correspondingly sensitive to the synergistic inhibition of glutathione and thioredoxin pathways. Lastly, a genome-wide CRISPR knockout screen identified the loss of NQO1 as a mechanism of LCS3 resistance. This work highlights the ability of TPP to uncover targets of small molecules identified by high-throughput screens and demonstrates the potential utility of inhibiting disulfide reductases as a therapeutic strategy for LUAD.
Project description:Thyroid carcinoma (TC) is generally associated with good prognosis, nevertheless no effective treatments are available for aggressive forms not cured by current therapies. We previously identified the coatomer protein complex zeta 1 (COPZ1), as a new putative therapeutic target for TC, since its depletion impairs the viability of tumor cells, leads to abortive autophagy, ER stress, unfolded protein response and apoptosis, and reduces the tumor growth of TC xenograft models. In this study, by combining genomic, proteomic and functional approaches, we provided evidence that COPZ1 silencing stimulates a type I IFN-mediated viral mimicry response, boosts the production of several inflammatory molecules and finally induces immunogenic cell death, which, in turn, promotes dendritic cell maturation and subsequent activation of T cells. Collectively, our findings support the notion that COPZ1 targeting can be exploited as a new strategy to kill cancer cells with the subsequent involvement of an anti-tumor immune response.