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DLD-1

RRID:CVCL_0248

Organism

Homo sapiens

Comments

Part of: AstraZeneca Colorectal cell line (AZCL) panel. Part of: Cancer Cell Line Encyclopedia (CCLE) project. Part of: MD Anderson Cell Lines Project. Doubling time: 20 hours (PubMed=427742); 33 hours (PubMed=25984343); ~48 hours (DSMZ). HLA typing: A*24:02,02:01; B*08:01,35:01; C*07:01,04:01 (PubMed=25960936). Microsatellite instability: Instable (MSI) (PubMed=10674020; PubMed=24042735; PubMed=28683746; PubMed=25926053). Sequence variation: Homozygous for ACVR2A p.Lys437fs*5 (c.1310delA) (PubMed=12615714). Sequence variation: APC p.Arg727Met (c.2180G>T), p.Lys993Asn (c.2979G>T), p.Ile1417fs*2 (c.4248delC) and p.Arg2166Ter (c.6496C>T) (PubMed=24755471). Sequence variation: Heterozygous for EP300 p.Glu1014Ter (c.4239A>G) (PubMed=10700188). Sequence variation: KRAS p.Gly13Asp (c.38G>A) (PubMed=12068308; PubMed=20570890; PubMed=24755471; PubMed=28683746). Sequence variation: PIK3CA p.Glu545Lys (c.1633G>A) and p.Asp549Asn (c.1645G>A) (PubMed=20570890; PubMed=24755471; PubMed=28683746). Sequence variation: Heterozygous for TGFBR2 p.Lys128Serfs*35 (c.383delA) (PubMed=12615714). Sequence variation: TP53 p.Ser241Phe (c.722C>T) (PubMed=16418264; PubMed=28683746). Omics: Deep proteome analysis. Omics: Deep RNAseq analysis. Omics: Deep phosphoproteome analysis. Omics: miRNA expression profiling. Omics: N-glycan profiling. Omics: Protein expression by reverse-phase protein arrays. Omics: shRNA library screening. Omics: SNP array analysis. Omics: Transcriptome analysis. Misspelling: DLD; In Cosmic 1571767 and Cosmic 1676737. Discontinued: RCB; RCB1957.

Proper Citation

TKG Cat# TKG 0379, RRID:CVCL_0248

Category

Cancer cell line

Sex

Male

Synonyms

DLD 1, DLD1, CoCL3

Vendor

TKG

Cat Num

TKG 0379

Cross References

BTO; BTO:0000391 CLO; CLO_0002785 EFO; EFO_0006389 MCCL; MCC:0000138 CLDB; cl1065 CLDB; cl1066 AddexBio; C0009007/36 ArrayExpress; E-MTAB-2706 ATCC; CCL-221 BCRC; 60132 BioSample; SAMN01821551 BioSample; SAMN01821680 BioSample; SAMN03472323 CCLE; DLD1_LARGE_INTESTINE CCRID; 3131C0001000700134 ChEMBL-Cells; CHEMBL3307580 ChEMBL-Targets; CHEMBL614285 ColonAtlas; DLD1 Cosmic; 687519 Cosmic; 755307 Cosmic; 870451 Cosmic; 873699 Cosmic; 876713 Cosmic; 905005 Cosmic; 913890 Cosmic; 934560 Cosmic; 948123 Cosmic; 983737 Cosmic; 985994 Cosmic; 1043810 Cosmic; 1066204 Cosmic; 1122323 Cosmic; 1154643 Cosmic; 1175839 Cosmic; 1184331 Cosmic; 1184082 Cosmic; 1187305 Cosmic; 1223137 Cosmic; 1310949 Cosmic; 1466813 Cosmic; 1479591 Cosmic; 1481418 Cosmic; 1519360 Cosmic; 1524004 Cosmic; 1552176 Cosmic; 1571767 Cosmic; 1609511 Cosmic; 1676737 Cosmic; 1805251 Cosmic; 2301544 Cosmic; 2301972 Cosmic; 2389573 Cosmic; 2464668 Cosmic; 2550352 Cosmic; 2646769 Cosmic; 2650774 Cosmic; 2651870 Cosmic; 2664050 Cosmic; 2667971 Cosmic; 2668249 Cosmic; 2727471 Cosmic; 2727478 DSMZ; ACC-278 ECACC; 90102540 GEO; GSM206467 GEO; GSM274715 GEO; GSM274716 GEO; GSM274727 GEO; GSM513817 GEO; GSM514291 GEO; GSM741247 GEO; GSM886979 GEO; GSM888048 GEO; GSM1346869 GEO; GSM1374463 GEO; GSM1448161 GEO; GSM2549997 ICLC; HTL95011 JCRB; JCRB9094 KCB; KCB 201196YJ KCLB; 10221 LINCS_LDP; LCL-1175 Lonza; 806 MetaboLights; MTBLS227 PRIDE; PXD000218 PRIDE; PXD001550 PRIDE; PXD005354 RCB; RCB1957 SKY/M-FISH/CGH; 1992 SKY/M-FISH/CGH; 2763 TKG; TKG 0379 TOKU-E; 1078 Wikidata; Q54831148

BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS-effector protein-protein interactions.

  • Bery N
  • Elife
  • 2018 Jul 10

Literature context: RRID:CVCL_0248


Abstract:

The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robust set of bioluminescence resonance energy transfer (BRET)-based RAS biosensors that enable monitoring of RAS-effector interaction inhibition in living cells. These include KRAS, HRAS and NRAS and a variety of different mutations that mirror those found in human cancers with the major RAS effectors such as CRAF, PI3K and RALGDS. We highlighted the utility of these RAS biosensors by showing a RAS-binding compound is a potent pan-RAS-effector interactions inhibitor in cells. The RAS biosensors represent a useful tool to investigate and characterize the potency of anti-RAS inhibitors in cells and more generally any RAS protein-protein interaction (PPI) in cells.

Funding information:
  • Bloodwise - 12051()
  • Medical Research Council - MR/J000612/1()
  • NIDDK NIH HHS - U24 DK059637(United States)
  • Wellcome - 099246/Z/12/Z()
  • Wellcome - 100842/Z/12/Z()

Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers.

  • Koundinya M
  • Cell Chem Biol
  • 2018 Jun 21

Literature context: esKP-4JCRBJCRB0182DLD-1ATCCATCC CCL-221PANC-1ATCCATCC CRL-1469CFPAC-1AT


Abstract:

Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways. In vivo preclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model.

Funding information:
  • Medical Research Council - (United Kingdom)

Erythropoietin Intensifies the Proapoptotic Activity of LFM-A13 in Cells and in a Mouse Model of Colorectal Cancer.

  • Tankiewicz-Kwedlo A
  • Int J Mol Sci
  • 2018 Apr 23

Literature context: anassas, VA, USA, Cat# CCL-221, RRID:CVCL_0248) and HT-29 (ATCC, Cat# HTB-38,


Abstract:

The Bruton’s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as an antileukemic agent, but applications in solid cancer have been found recently. The compound promotes apoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs. We decided to assess the impact of the simultaneous use of erythropoietin (Epo) and LFM-A13 on signal transduction in colon DLD-1 and HT-29 cells, as well as in tumor xenografts. The induction of apoptosis by Epo and LFM-A-13 in the cells was confirmed by phosphatidylserine externalization, loss of mitochondrial membrane potential, and modulation of the expression of apoptotic protein BAX and antiapoptotic protein BCL-2 in colon adenocarcinoma cells. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM-A13 in order to evaluate the degree of tumor regression. The simultaneous use of Epo and LFM-A13 severely inhibited cell growth, activated apoptosis, and also inhibited tumor growth in xenografts. The addition of Epo to LFM-A13 intensified the antiproliferative effect of LFM-A13, confirmed by the loss of mitochondrial membrane potential and the accumulation of apoptotic colon cancer cells with externalized phosphatidylserine (PS). These preclinical results suggest that the combination of Epo and LFM-A13 has a high proapoptotic activity and should be tested in the clinic for the treatment of solid tumors such as colon cancer.

Funding information:
  • Intramural NIH HHS - Z99 CA999999(United States)

Loss of TET1 facilitates DLD1 colon cancer cell migration via H3K27me3-mediated down-regulation of E-cadherin.

  • Zhou Z
  • J. Cell. Physiol.
  • 2018 Feb 17

Literature context: CCL-221, RRID:CVCL_0248) were cult


Abstract:

Epigenetic modifications such as histone modifications and cytosine hydroxymethylation are linked to tumorigenesis. Loss of 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation 1 (TET1) down-regulation facilitates tumor initiation and development. However, the mechanisms by which loss of TET1 knockdown promotes malignancy development remains unclear. Here, we report that TET1 knockdown induced epithelial-mesenchymal transition (EMT) and increased cancer cell growth, migration, and invasion in DLD1 cells. Loss of TET1 increased EZH2 expression and reduced UTX-1 expression, thus increasing histone H3K27 tri-methylation causing repression of the target gene E-cadherin. Ectopic expression of the H3K27 demethylase UTX-1 or EZH2 depletion both impeded EZH2 binding caused a loss of H3K27 methylation at epithelial gene E-cadherin promoter, thereby suppressing EMT and tumor invasion in shTET1 cells. Conversely, UTX-1 depletion and ectopic expression of EZH2 enhanced EMT and tumor metastasis in DLD1 cells. These findings provide insight into the regulation of TET1 and E-cadherin and identify EZH2 as a critical mediator of E-cadherin repression and tumor progression.

MELK expression correlates with tumor mitotic activity but is not required for cancer growth.

  • Giuliano CJ
  • Elife
  • 2018 Feb 8

Literature context: Cell line (human) DLD1 ATCC RRID:CVCL_0248


Abstract:

The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Previously, we established that triple-negative breast cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK proliferate at wild-type levels in vitro (Lin et al., 2017). Here, we generate several additional knockout clones of MELK and demonstrate that across cancer types, cells lacking MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. By combining our MELK-knockout clones with a recently described, highly specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cohorts of cancer patients identifies MELK expression as a correlate of tumor mitotic activity, explaining its association with poor clinical prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies.

Funding information:
  • NIDDK NIH HHS - R01 DK088718(United States)
  • NIH Office of the Director - 1DP5OD021385()

Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling.

  • Lee G
  • Cell
  • 2017 Dec 14

Literature context: DLD1 ATCC Cat#CCL-221; RRID:CVCL_0248 A549 ATCC Cat#CCL-185; RRID: CV


Abstract:

mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense-mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders.

Funding information:
  • NHLBI NIH HHS - R01 HL074894(United States)

Simultaneous use of erythropoietin and LFM-A13 as a new therapeutic approach for colorectal cancer.

  • Tankiewicz-Kwedlo A
  • Br. J. Pharmacol.
  • 2017 Nov 22

Literature context: DLD-1 (ATCC, Cat# CCL-221, RRID:CVCL_0248) and HT-29 (ATCC, Cat# HTB-38,


Abstract:

BACKGROUND AND PURPOSE: Bruton's tyrosine kinase (Btk) is a non-receptor tyrosine kinase involved in the activation of signalling pathways responsible for cell maturation and viability. Btk has previously been reported to be overexpressed in colon cancers. This kind of cancer is often accompanied by anaemia, which is treated with an erythropoietin supplement. The goal of the present study was to assess the effects of combination therapy with erythropoietin β (Epo) and LFM-A13 (Btk inhibitor) on colon cancer in in vitro and in vivo models. EXPERIMENTAL APPROACH: DLD-1 and HT-29 human colon adenocarcinoma cells were cultured with Epo and LFM-A13. Cell number and viability, and mRNA and protein levels of Epo receptors, Btk and Akt were assessed. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM-A13. KEY RESULTS: The combination of Epo and LFM-A13 mostly exerted a synergistic inhibitory effect on colon cancer cell growth. The therapeutic scheme used effectively killed the cancer cells and attenuated the Btk signalling pathways. Epo + LFM-A13 also prevented the normal process of microtubule assembly during mitosis by down-regulating the expression of Polo-like kinase 1. The combination of Epo and LFM-A13 significantly reduced the growth rate of tumour cells, while it showed high safety profile, inducing no nephrotoxicity, hepatotoxicity or changes in the haematological parameters. CONCLUSION AND IMPLICATIONS: Epo significantly enhances the antitumour activity of LFM-A13, indicating that a combination of Epo and LFM-A13 has potential as an effective therapeutic approach for patients with colorectal cancer.

Cell Permeable Stapled Peptide Inhibitor of Wnt Signaling that Targets β-Catenin Protein-Protein Interactions.

  • Dietrich L
  • Cell Chem Biol
  • 2017 Aug 17

Literature context: nesDLD-1ATCCCat#ATCC® CCL-221™; RRID: CVCL_0248SW-480DSMZCat#313; RRID: CVCL_05


Abstract:

The Wnt signaling pathway plays a critical role in cell proliferation and differentiation, thus it is often associated with diseases such as cancers. Unfortunately, although attractive, developing anti-cancer strategy targeting Wnt signaling has been challenging given that the most attractive targets are involved in protein-protein interactions (PPIs). Here, we develop a stapled peptide inhibitor that targets the interaction between β-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling. Our integrative approach combines peptide stapling to optimize proteolytic stability, with lessons learned from cell-penetrating peptide (CPP) design to maximize cellular uptake resulting in NLS-StAx-h, a selective, cell permeable, stapled peptide inhibitor of oncogenic Wnt signaling that efficiently inhibits β-catenin-transcription factor interactions. We expect that this type of integrative strategy that endows stapled peptides with CPP features will be generally useful for developing inhibitors of intracellular PPIs.

Eradication of Tumors through Simultaneous Ablation of CD276/B7-H3-Positive Tumor Cells and Tumor Vasculature.

  • Seaman S
  • Cancer Cell
  • 2017 Apr 10

Literature context: CCL-221; RRID:CVCL_0248 SW620 ATCC


Abstract:

Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature. In contrast, pyrrolobenzodiazepine-conjugated CD276 ADCs killed both cancer cells and tumor vasculature, eradicating large established tumors and metastases, and improving long-term overall survival. CD276-targeted dual-compartment ablation could aid in the development of highly selective broad-acting anti-cancer therapies.

Funding information:
  • Intramural NIH HHS - ZIA BC010578-13()
  • Intramural NIH HHS - ZIA BC010736-11()

Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression.

  • Poh AR
  • Cancer Cell
  • 2017 Apr 10

Literature context: 247DLD1Prof. Oliver SieberATCC #CCL-221SW480Prof. Oliver SieberATCC #CC


Abstract:

Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.

Funding information:
  • NIAID NIH HHS - R01 AI065495()
  • NIAID NIH HHS - R01 AI068150()

A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis.

  • Treiber T
  • Mol. Cell
  • 2017 Apr 20

Literature context: CC® HTB-22human: DLD-1ATCCATCC® CCL-221human: LN-229our labATCC® CRL-26


Abstract:

During microRNA (miRNA) biogenesis, two endonucleolytic reactions convert stem-loop-structured precursors into mature miRNAs. These processing steps can be posttranscriptionally regulated by RNA-binding proteins (RBPs). Here, we have used a proteomics-based pull-down approach to map and characterize the interactome of a multitude of pre-miRNAs. We identify ∼180 RBPs that interact specifically with distinct pre-miRNAs. For functional validation, we combined RNAi and CRISPR/Cas-mediated knockout experiments to analyze RBP-dependent changes in miRNA levels. Indeed, a large number of the investigated candidates, including splicing factors and other mRNA processing proteins, have effects on miRNA processing. As an example, we show that TRIM71/LIN41 is a potent regulator of miR-29a processing and its inactivation directly affects miR-29a targets. We provide an extended database of RBPs that interact with pre-miRNAs in extracts of different cell types, highlighting a widespread layer of co- and posttranscriptional regulation of miRNA biogenesis.

Palmitoylated SCP1 is targeted to the plasma membrane and negatively regulates angiogenesis.

  • Liao P
  • Elife
  • 2017 Mar 31

Literature context: D1 cells (RRID:CVCL-0248) were cult


Abstract:

SCP1 as a nuclear transcriptional regulator acts globally to silence neuronal genes and to affect the dephosphorylation of RNA Pol ll. However, we report the first finding and description of SCP1 as a plasma membrane-localized protein in various cancer cells using EGFP- or other epitope-fused SCP1. Membrane-located SCP1 dephosphorylates AKT at serine 473, leading to the abolishment of serine 473 phosphorylation that results in suppressed angiogenesis and a decreased risk of tumorigenesis. Consistently, we observed increased AKT phosphorylation and angiogenesis followed by enhanced tumorigenesis in Ctdsp1 (which encodes SCP1) gene - knockout mice. Importantly, we discovered that the membrane localization of SCP1 is crucial for impeding angiogenesis and tumor growth, and this localization depends on palmitoylation of a conserved cysteine motif within its NH2 terminus. Thus, our study discovers a novel mechanism underlying SCP1 shuttling between the plasma membrane and nucleus, which constitutes a unique pathway in transducing AKT signaling that is closely linked to angiogenesis and tumorigenesis.

Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases.

  • Clarke PA
  • Elife
  • 2016 Dec 9

Literature context: 5 - RRID:CVCL_0218; DLD1 - RRID:CVCL_0248; HT29 - RRID:CVCL_0320; LS174T


Abstract:

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.

Funding information:
  • NINDS NIH HHS - NS080889(United States)

Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer.

  • Berger S
  • Elife
  • 2016 Nov 2

Literature context: CC, RRID:CVCL_0248), RKO (ATC


Abstract:

Many cancers overexpress one or more of the six human pro-survival BCL2 family proteins to evade apoptosis. To determine which BCL2 protein or proteins block apoptosis in different cancers, we computationally designed three-helix bundle protein inhibitors specific for each BCL2 pro-survival protein. Following in vitro optimization, each inhibitor binds its target with high picomolar to low nanomolar affinity and at least 300-fold specificity. Expression of the designed inhibitors in human cancer cell lines revealed unique dependencies on BCL2 proteins for survival which could not be inferred from other BCL2 profiling methods. Our results show that designed inhibitors can be generated for each member of a closely-knit protein family to probe the importance of specific protein-protein interactions in complex biological processes.

Funding information:
  • NIDDK NIH HHS - R21 DK106584(United States)