Liver lineage confers sensitivity of cancer cells to sulfonation-dependent alkylators
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ABSTRACT:
PROVIDER: PRJNA714004 | ENA |
REPOSITORIES: ENA
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Project description:Adult liver malignancies, including intrahepatic cholangiocarcinoma and hepatocellular carcinoma, are the 2nd leading cause of cancer related death worldwide. The majority of patients are currently treated with either combination chemotherapy or immunotherapy, respectively, without specific biomarkers for patient selection. Here, using high-throughput screens, proteomics, and in vitro resistance models, we identify the small molecule, YC-1, as selectively active against a defined subset of cell lines derived from both major liver cancer types. We demonstrate that selectivity in vitro and in vivo is determined by expression of a human cytosolic sulfotransferase – the liver resident enzyme SULT1A1, which sulfonates YC-1. Sulfonation stimulates covalent binding of YC-1 to lysine residues in protein targets, enriching for RNA binding factors. Using computational analysis as well as structural modeling, we also define a wider group of structurally related SULT1A1-activated small molecules with distinct target profiles, which together constitute an untapped small molecule class. These studies provide a foundation for pre-clinical development of these agents and point to the broader potential of exploiting the liver lineage enzyme SULT1A1 for selective targeting strategies.
2023-01-24 | GSE168791 | GEO
Project description:The small molecule YC-1 was identified as identified as a selectively active agent against subsets of the two major live cancer subtypes, intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Response to YC-1 is dependent on the expression of the sulfotransferase SULT1A1, which activates YC-1 through sulfonation. The contributions of mass spectrometry to the study were: (i) identifying SULT1A1 as the key player in YC-1 response through observing the protein in a cell line with acquired resistance to the small molecule treatment, (ii) corroborating the role of SULT1A1 in the YC-1 activity by correlating protein expression profiles and drug responses across 37 biliary cancer cell lines, (iii) showing that SULT1A1 expression was associated with IDH mutations, FGFR2 fusion, and BAP1 loss in vivo studying patient-derived xenograft (PDX) models, and (iv) identifying protein targets in a protein enrichment experiment with an immobilized drug.
(i) and (ii): Cell line samples from datasets (i) and (ii) were analyzed together in a set of 12 TMT sets (ShiBardeesy_CellLines_TMT1 to TMT12) using TMT11-barcoding. The samples were analyzed on an Orbitrap Lumos mass spectrometer using the SPS-MS3 method. Prior to analysis, samples were fractionated offline using high pH reversed chromatography (12 fractions per TMT set). Across all TMT sets, channel 131c was used as the bridge channel (pooled digests of all samples). Samples were labeled as follows (rep = replicate:
(i) Cell lines samples with acquired resistance to YC-1 treatment:
ShiBardeesy_CellLines_TMT1: RBE_rep_1 (126), RBE YC1 Resistant 6_rep_1 (129c).
ShiBardeesy_CellLines_TMT2: RBE YC1 Resistant 3_rep_1 (129n), RBE YC1 Resistant 1_rep_1 (130n).
ShiBardeesy_CellLines_TMT3: RBE YC1 Resistant 2_rep_1 (126), RBE YC1 Resistant 5_rep_1 (130c).
ShiBardeesy_CellLines_TMT4: RBE YC1 Resistant 4_rep_1 (126).
ShiBardeesy_CellLines_TMT5: RBE YC1 Resistant 1_rep_2 (127n), RBE YC1 Resistant 4_rep_2 (128c), RBE YC1 Resistant 3_rep_2 (130c).
ShiBardeesy_CellLines_TMT6: RBE YC1 Resistant 2_rep_2 (126), RBE YC1 Resistant 6_rep_2 (127c).
ShiBardeesy_CellLines_TMT7: RBE_rep_2 (128n), RBE YC1 Resistant 5_rep_2 (130n).
(ii) Proteomes of untreated biliary cell lines (baseline):
ShiBardeesy_CellLines_TMT1: RBE_rep_1 (126), GB2_rep_1 (127n), HuCCT1_rep_1 (127c), ECC3_rep_1 (128n), ICC10_rep_1 (128c), KMCH-1_rep_1 (129n), SNU-1196_rep_1 (130n).
ShiBardeesy_CellLines_TMT2: ICC13-7_rep_1 (126), ICC8_rep_1 (127n), ICC9_rep_1 (127c), SNU-478_rep_1 (128n), CC-SW-1_rep_1 (128c), CC-LP-1_rep_1 (129c), SSP-25_rep_1 (130c), ICC10-8_rep_1 (131n)
ShiBardeesy_CellLines_TMT3: SNU-1079_rep_1 (127n), ICC5_rep_1 (127c), ICC7_rep_1 (128c), COR-L105_rep_1 (129n), ICC17_rep_1 (129c), GBC1_rep_1 (131n).
ShiBardeesy_CellLines_TMT4: ICC3_rep_1 (127n), ICC2_rep_1 (127c), ICC106_rep_1 (128n), ICC11_rep_1 (128c), HKGZ-CC_rep_1 (129n), SNU-869_rep_1 (129c), HuH28_rep_1 (130n), ICC12_rep_1 (130c), SNU-308_rep_1 (131n).
ShiBardeesy_CellLines_TMT5: ICC2_rep_2 (126), ECC3_rep_2 (127c), GB2_rep_2 (128n), ICC11_rep_2 (129n), ICC7_rep_2 (129c), SNU-869_rep_2 (130n), SSP-25_rep_2 (131n).
ShiBardeesy_CellLines_TMT6: CC-LP-1_rep_2 (127n), COR-L105_rep_2 (128n), HuCCT1_rep_2 (129n), ICC12_rep_2 (129c), ICC3_rep_2 (131n), ICC5_rep_2 (130n), SNU-478_rep_2 (130c).
ShiBardeesy_CellLines_TMT7: ICC10_rep_2 (126), ICC10-6_rep_2 (127n), ICC10-8_rep_2 (127c), RBE_rep_2 (128n), ICC9_rep_2 (128c), ICC17_rep_2 (129n), ICC8_rep_2 (129c), CC-SW-1_rep_2 (130c), GBC1_rep_2 (131n).
ShiBardeesy_CellLines_TMT8: ICC13-7_rep_2 (127c), HuH28_rep_2 (128n), HKGZ-CC_rep_2 (128c), SNU-1079_rep_2 (129n), KMCH-1_rep_2 (129c), SNU-1196_rep_2 (130n), SNU-308_rep_2 (131n).
ShiBardeesy_CellLines_TMT9: SG231_rep_1 (126), KKU-100_rep_1 (127n), YSCCC_rep_1 (127c), ICC4_rep_1 (128n), TKKK_rep_1 (128c), ECC2_rep_1 (129n), KKU-M213/M214 (129c).
ShiBardeesy_CellLines_TMT10: YSCCC_rep_2 (126), KKU-M213/M214_rep_2 (127n), SG231_rep_2 (127c), TKKK_rep_2 (129n), ECC2_rep_2 (129c), ICC4_rep_2 (130n), KKU-100_rep_2 (131n).
ShiBardeesy_CellLines_TMT11: ICC13-7_rep_1 (129n).
ShiBardeesy_CellLines_TMT12: ICC13-7_rep2 (131n)
2022-11-29 | MSV000090805 | MassIVE
Project description:The small molecule YC-1 was identified as identified as a selectively active agent against subsets of the two major live cancer subtypes, intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Response to YC-1 is dependent on the expression of the sulfotransferase SULT1A1, which activates YC-1 through sulfonation. The contributions of mass spectrometry to the study were: (i) identifying SULT1A1 as the key player in YC-1 response through observing the protein in a cell line with acquired resistance to the small molecule treatment, (ii) corroborating the role of SULT1A1 in the YC-1 activity by correlating protein expression profiles and drug responses across 37 biliary cancer cell lines, (iii) showing that SULT1A1 expression was associated with IDH mutations, FGFR2 fusion, and BAP1 loss in vivo studying patient-derived xenograft (PDX) models, and (iv) identifying protein targets in a protein enrichment experiment with an immobilized drug.
(iii) PDX samples were analyzed using TMT multiplexing on an Orbitrap Fusion mass spectrometer using the SPS-MS3 method. Prior to analysis, samples were fractionated offline using high pH reversed chromatography (12 fractions per TMT set). Three TMT sets were analyzed (ShiBardeesy_PDX_TMT1, ShiBardeesy_PDX_TMT2, and ShiBardeesy_PDX_TMT3), and samples were labeled as follows with channel (bridge channel, 130c):
ShiBardeesy_PDX_TMT1: SS101 (126), MG12 (127c), SS106 (127n), MG62 (128c), MG26 (128n), LCCH13 (129c), LCCH3 (129n), Q12050 (130n).
ShiBardeesy_PDX_TMT2: SS102 (126), SS110 (127n), MG34 (128c), MG17 (128n), LCCH4 (129c), MG68 (129n), HBT110 (130n).
ShiBardeesy_PDX_TMT3: SS103 (126), MG10 (127n), MG59 (128c), MG25 (128n), LCCH10 (129c), MG73 (129n), HBT211 (130n).
(iv) Samples from experiments using immobilized small molecules to determine direct interactors of YC-1 were performed using TMT10-barcoding and the SPS-MS3 method on an Orbitrap Lumos mass spectrometer. No off-line fraction was performed. Samples were grouped into two TMT sets (ShiBardeesy_ImmobilizedDrug_TMT1 and ShiBardeesy_ImmobilizedDrug_TMT2). Channel 131N was used as the bridge channel. Samples were labeled as follows:
ShiBardeesy_ImmobilizedDrug_TMT1: immobilized_inactiveYC-1_rep_1 (126), immobilized_inactiveYC-1_rep_2 (128n), immobilized_inactiveYC-1_rep_3 (128c), immobilized_YC-1_rep_1 (129n), immobilized_YC-1_plus_soluble_YC-1_competitor_rep_1 (130c).
ShiBardeesy_ImmobilizedDrug_TMT2: immobilized_YC-1_rep_2 (127n), immobilized_YC-1_plus_soluble_YC-1_competitor_rep_2 (128n), immobilized_YC-1_plus_soluble_YC-1_competitor_rep_3 (129c), immobilized_YC-1_rep_3 (130c).
2022-11-29 | MSV000090808 | MassIVE
Project description:EZH2 inhibition confers PIK3CA-driven lung tumors enhanced sensitivity to PI3K inhibition
| PRJNA762053 | ENA
Project description:Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition
| PRJNA1073893 | ENA
Project description:Classification of human liver cancer into biologically distinct subgroups suggests origin from different hepatic lineage cells. To clarify contribution of lineage stage in liver oncogenesis, we transduced H-Ras and SV40LT into hepatic progenitor cells (HPC), hepatoblasts (HB) and terminally differentiated adult hepatocytes (AH). Regardless of origin, all transformed cell types acquired common cancer stem cell characteristics in vitro and in vivo. However, expression analysis distinguished tumors of different cellular origin underscoring the contribution of lineage/stage-dependent genetic changes in malignant transformation. Notably, AH-derived tumors showed specific enrichment of c-Myc target genes. These data establish that any hepatic lineage cell can be a target for transformation and acquire common cancer stem cell traits via activation of diverse cell type specific pathways. Profiling of individual tumors derived by Ras/SV40 transformation of hepatic progenitor cell (oval cells), hepatoblasts (fetal) and adult hepatocytes
2013-10-01 | E-GEOD-41312 | biostudies-arrayexpress
Project description:primary ALL cells (B-lineage) resistant to vincristine by the MTT in vitro sensitivity assay
2008-06-15 | E-GEOD-658 | biostudies-arrayexpress
Project description:Hepatic p53 protein level governs liver s sensitivity to drug-induced liver injury
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Project description:primary ALL cells (B- and T-lineage) resistant to vincristine by the MTT in vitro sensitivity assay
2008-06-14 | E-GEOD-649 | biostudies-arrayexpress
Project description:WalKR is a two-component system that is essential for viability in Gram-positive bacteria that regulates the all-important autolysins. Here we show a T101M mutation in walR confers a defect in autolysis, a thickened cell wall and decreased sensitivity to antibiotics that target the lipid II cycle, a phenotype that is reminiscent of the clinical resistance form known as vancomycin intermediate-resistant Staphylococcus aureus. Importantly, this is accompanied by dramatic sensitization to tunicamycin. We demonstrate that this phenotype is due to partial collapse of a pathway consisting of autolysins, AtlA and Sle1, a transmembrane sugar permease, MurP, and GlcNAc recycling enzymes, MupG and MurQ. We suggest that this causes a shortage of substrate for MraY causing it to be hypersensitive to competitive inhibition by tunicamycin. This constitutes a new molecular model for antibiotic sensitivity in S. aureus and a promising new route for antibiotic discovery.
2022-08-25 | GSE211745 | GEO