Response of LUAD cells to LCS3
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ABSTRACT:
PROVIDER: PRJNA738470 | ENA |
REPOSITORIES: ENA
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Project description:High-throughput phenotype-based screening of large libraries of compounds 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 effector 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 screen identified the loss of NQO1 as a mechanism of LCS3 resistance. This work highlights the power of TPP to uncover targets of small molecules identified by high-throughput screens and demonstrates the potential utility of inhibiting disulfide reductases in treatment of LUAD.
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Project description:Lung cancer is the leading cause of cancer-related death in the United States. Long non-coding RNAs (lncRNAs) are a class of regulatory molecules whose role in lung carcinogenesis is poorly understood. In this study, we profiled lncRNA expression in lung adenocarcinoma (LUAD) cell lines, compared their expression to that of purified alveolar epithelial type II cells (the purported cell of origin for LUAD), cross-referenced these with lncRNAs altered in primary human tumors, and interrogated for lncRNA whose expression correlated with patient survival. We identified LINC00261, a lncRNA with unknown function in LUAD, adjacent to the pioneering transcription factor FOXA2. Loss of LINC00261 was observed in multiple tumor types, including liver, breast, and gastric cancer. Reintroduction of LINC00261 into human LUAD cell lines inhibited cell migration and slowed proliferation by inducing a G2/M cell cycle arrest while upregulating DNA damage pathway genes and inducing phosphorylation-mediated activation of components of the DNA damage pathway. FOXA2 was able to induce LINC00261 expression, and the entire locus underwent hypermethylation in LUAD, leading to loss of expression. We have thus identified an epigenetically deregulated lncRNA, whose loss of expression in LUAD promotes the malignant phenotype and blocks activation of the DNA damage machinery, predisposing lung cells to cancer development.
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Project description:Targeting protein for Xklp2 (TPX2) is a mitotic regulator frequently overexpressed in lung adenocarcinoma (LUAD), while its role in cancer stemness and autophagy remains incompletely understood. In this study, integrative bioinformatic analyses based on TCGA and GTEx datasets revealed that TPX2 overexpression in LUAD was associated with poor prognosis, elevated stemness scores, and increased expression of cancer stem cell-related markers. To investigate the molecular mechanisms underlying TPX2-mediated regulation in LUAD, RNA sequencing was performed in PC9 cells following TPX2 knockdown. Transcriptomic profiling and pathway analyses identified significant alterations in autophagy-related signaling pathways. In parallel, co-immunoprecipitation coupled with mass spectrometry (IP-MS) was conducted to characterize TPX2-associated protein interactions and explore potential regulatory networks involved in autophagy. Functional experiments further demonstrated that TPX2 depletion impaired autophagic flux and reduced stemness-associated phenotypes in LUAD cells, whereas TPX2 overexpression exerted opposite effects. These data provide transcriptomic and proteomic resources for investigating the role of TPX2-mediated autophagy in LUAD progression and cancer stemness.
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Project description:<p><a href="https://cptac-data-portal.georgetown.edu/study-summary/S056" target="_blank">Proteogenomics of Lung Adenocarcinoma, Gillette et al., 2020 publication is here</a><br><br>Lung cancer is a leading cause of cancer death in the United States and in 2019 it is estimated that there will be over 228,000 new cases (<a href="https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html" target="_blank">American Cancer Society</a>). There are two main types, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). A majority of patients (85%) have NSCLC, with a significant portion of those individuals having a histological subtype lung adenocarcinoma (LUAD) <a href="https://www.ncbi.nlm.nih.gov/pubmed/29364287" target="_blank">Herbst et al., 2018 Nature</a>. To advance the proteogenomic understanding of LUAD, the CPTAC program has investigated 111 tumors, (with 102 tumors paired with normal adjacent tissue samples) and subjected these samples to global proteome and phosphoproteome analysis. An optimized workflow for mass spectrometry of tissues using isobaric tags (TMT (tandem mass tags)-10) was used (<a href="https://www.ncbi.nlm.nih.gov/pubmed/29988108" target="_blank">Mertins et al., Nature Protocols 2018</a>). Proteome and phosphoproteome data from the LUAD discovery cohort is available below along with peptide spectrum matches (PSMs) and protein summary reports from the CPTAC common data analysis pipeline (CDAP).</p><p><em>Clinical Data</em> for LUAD tumors are provided below. Updates will be available as the LUAD cohort characterization proceeds.<br><em>Genomic Data</em> for LUAD tumors is available from the NCI Genomic Data Commons (GDC), <a href="https://portal.gdc.cancer.gov/projects/CPTAC-3" target="_blank">here</a><br><em>Imaging Data</em> for LUAD tumors is available from NCI, The Cancer Imaging Archive (TCIA), <a href="https://wiki.cancerimagingarchive.net/display/Public/CPTAC-LUAD" target="_blank">here</a><br>This release includes over 4500 files and 914 GB of data.</p>
<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/study-summary/S046">https://cptac-data-portal.georgetown.edu/study-summary/S046</a> on 01/29/21</li></ul>
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