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A-375

RRID:CVCL_0132

Organism

Homo sapiens

Comments

Part of: Cancer Cell Line Encyclopedia (CCLE) project. Part of: COSMIC cell lines project. Part of: MD Anderson Cell Lines Project. Part of: Naval Biosciences Laboratory (NBL) collection (transferred to ATCC in 1982). Doubling time: 26.9 +- 6.9 hours (PubMed=29275043); ~32 hours (PBCF). HLA typing: A*01:01,02:01; B*57:01,44:03; C*16:02,06:02; DQA1*03:02,02:01; DQB1*03:03,03:03; DRB1*04:05,07:01 (PubMed=25960936). Microsatellite instability: Stable (MSS) (Sanger). Sequence variation: Homozygous for BRAF p.Val600Glu (c.1799T>A) (ATCC; PubMed=29492214). Sequence variation: Homozygous for CDKN2A p.Glu61Ter (c.181G>T) (p.Gly75Val; c.224G>T) and p.Glu69Ter (c.205G>T) (p.Gly83Val; c.248G>T) (ATCC; PubMed=29492214). Omics: Array-based CGH. Omics: Deep exome analysis. Omics: Deep proteome analysis. Omics: Deep RNAseq analysis. Omics: DNA methylation analysis. Omics: Protein expression by reverse-phase protein arrays. Omics: Secretome proteome analysis. Omics: SNP array analysis. Omics: Transcriptome analysis. Discontinued: ATCC; CRL-7904.

Proper Citation

ATCC Cat# CRL-1619, RRID:CVCL_0132

Category

Cancer cell line

Sex

Female

Synonyms

A 375, A375, A375-MEL, A375-mel, A375mel

Vendor

ATCC

Cat Num

CRL-1619

Cross References

BTO; BTO:0002806 CLO; CLO_0001544 CLO; CLO_0001581 CLO; CLO_0001582 EFO; EFO_0002103 MCCL; MCC:0000024 CLDB; cl198 CLDB; cl199 ArrayExpress; E-MTAB-2706 ArrayExpress; E-MTAB-2770 ArrayExpress; E-MTAB-3610 ATCC; CRL-1619 ATCC; CRL-7904 BCRC; 60039 BCRJ; 0278 BioSample; SAMN03472142 BioSample; SAMN05292441 CCLE; A375_SKIN CCRID; 3111C0001CCC000126 CCRID; 3111C0001CCC000327 CCRID; 3131C0001000700004 CCRID; 3131C0001000700155 CGH-DB; 9313-4 ChEMBL-Cells; CHEMBL3308077 ChEMBL-Targets; CHEMBL613859 ChEMBL-Targets; CHEMBL1075388 CLS; 300110/p852_A-375 Cosmic; 686480 Cosmic; 687431 Cosmic; 706114 Cosmic; 876698 Cosmic; 888861 Cosmic; 897482 Cosmic; 897735 Cosmic; 905226 Cosmic; 906793 Cosmic; 928688 Cosmic; 933003 Cosmic; 1006556 Cosmic; 1022280 Cosmic; 1054855 Cosmic; 1132587 Cosmic; 1155278 Cosmic; 1211162 Cosmic; 1303032 Cosmic; 1458961 Cosmic; 1459655 Cosmic; 1477406 Cosmic; 1481413 Cosmic; 1507620 Cosmic; 1537486 Cosmic; 1555009 Cosmic; 1669118 Cosmic; 1812178 Cosmic; 1888914 Cosmic; 1890486 Cosmic; 1989294 Cosmic; 1995332 Cosmic; 2036699 Cosmic; 2230112 Cosmic; 2233660 Cosmic; 2479252 Cosmic-CLP; 906793 ECACC; 88113005 ENCODE; ENCBS606AAA ENCODE; ENCBS607AAA GDSC; 906793 GEO; GSM206443 GEO; GSM218051 GEO; GSM274681 GEO; GSM276771 GEO; GSM555173 GEO; GSM827158 GEO; GSM886854 GEO; GSM887919 GEO; GSM952580 GEO; GSM1092559 GEO; GSM1138787 GEO; GSM1374382 GEO; GSM1669582 IGRhCellID; A375 IZSLER; BS TCL 88 KCB; KCB 99003YJ LINCS_HMS; 50060 LINCS_LDP; LCL-1235 Lonza; 970 NCBI_Iran; C136 PRIDE; PXD001485 PRIDE; PXD004343 Wikidata; Q54605986

Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation.

  • Zeng H
  • Cancer Cell
  • 2018 Jul 9

Literature context: tianN/ASK-MEL5ATCCHTB-70A375ATCCCRL-1619293TATCCCRL-3216MCF10AATCCCRL103


Abstract:

Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16INK4A permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2.

Funding information:
  • NIAMS NIH HHS - N01-AR-1-2256(United States)

An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential.

  • Wang L
  • Cell
  • 2018 May 31

Literature context: A375 ATCC RRID:CVCL_0132 (Female cell line)


Abstract:

BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.

Funding information:
  • NINDS NIH HHS - R01 NS026799(United States)

Overcoming Resistance to Targeted Anticancer Therapies through Small-Molecule-Mediated MEK Degradation.

  • Peh J
  • Cell Chem Biol
  • 2018 May 18

Literature context: Models: Cell LinesA375ATCCCat # CRL-1619K-562ATCCCat # CCL-243PC-9 GRPro


Abstract:

The discovery of mutant or fusion kinases that drive oncogenesis, and the subsequent approval of specific inhibitors for these enzymes, has been instrumental in the management of some cancers. However, acquired resistance remains a significant problem in the clinic, limiting the long-term effectiveness of most of these drugs. Here we demonstrate a general strategy to overcome this resistance through drug-induced MEK cleavage (via direct procaspase-3 activation) combined with targeted kinase inhibition. This combination effect is shown to be general across diverse tumor histologies (melanoma, lung cancer, and leukemia) and driver mutations (mutant BRAF or EGFR, fusion kinases EML4-ALK and BCR-ABL). Caspase-3-mediated degradation of MEK kinases results in sustained pathway inhibition and substantially delayed or eliminated resistance in cancer cells in a manner far superior to combinations with MEK inhibitors. These data suggest the generality of drug-mediated MEK kinase cleavage as a therapeutic strategy to prevent resistance to targeted anticancer therapies.

Funding information:
  • NCI NIH HHS - R01 CA120439()
  • NIAID NIH HHS - R01-AI043356(United States)
  • NIGMS NIH HHS - T32 GM070421()

Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy.

  • Cascone T
  • Cell Metab.
  • 2018 May 1

Literature context: ATCC CRL-1619; RRID:CVCL_0132 Experimental Models: Organisms/


Abstract:

Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo. Moreover, glycolysis-related gene expression was higher in melanoma tissues from ACT-refractory patients, and tumor cells derived from these patients exhibited higher glycolytic activity. We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells. Our findings demonstrate that tumor glycolysis is associated with the efficacy of ACT and identify the glycolysis pathway as a candidate target for combinatorial therapeutic intervention.

Funding information:
  • European Research Council - 243211(International)
  • NCI NIH HHS - P50 CA070907()
  • NCI NIH HHS - P50 CA093459()
  • NCI NIH HHS - R01 CA184845()
  • NCI NIH HHS - R01 CA187076()

Cancer-Germline Antigen Expression Discriminates Clinical Outcome to CTLA-4 Blockade.

  • Shukla SA
  • Cell
  • 2018 Apr 19

Literature context: a cell line ATCC Cat# CRL-1619, RRID:CVCL_0132 Experimental Models: Organisms/


Abstract:

CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.

Funding information:
  • NICHD NIH HHS - K12HD00849(United States)

A Library of Phosphoproteomic and Chromatin Signatures for Characterizing Cellular Responses to Drug Perturbations.

  • Litichevskiy L
  • Cell Syst
  • 2018 Apr 25

Literature context: t melanoma) ATCC Cat# CRL-1619; RRID:CVCL_0132 Human A549 (non-small-cell lung


Abstract:

Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the "connectivity" framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics.

Funding information:
  • NINDS NIH HHS - NS32092(United States)

The Dietary Supplement Chondroitin-4-Sulfate Exhibits Oncogene-Specific Pro-tumor Effects on BRAF V600E Melanoma Cells.

  • Lin R
  • Mol. Cell
  • 2018 Mar 15

Literature context: A375 cells ATCC Cat# CRL-1619; RRID:CVCL_0132 Human: SK-MEL-5 cells ATCC Cat#


Abstract:

Dietary supplements such as vitamins and minerals are widely used in the hope of improving health but may have unidentified risks and side effects. In particular, a pathogenic link between dietary supplements and specific oncogenes remains unknown. Here we report that chondroitin-4-sulfate (CHSA), a natural glycosaminoglycan approved as a dietary supplement used for osteoarthritis, selectively promotes the tumor growth potential of BRAF V600E-expressing human melanoma cells in patient- and cell line-derived xenograft mice and confers resistance to BRAF inhibitors. Mechanistically, chondroitin sulfate glucuronyltransferase (CSGlcA-T) signals through its product CHSA to enhance casein kinase 2 (CK2)-PTEN binding and consequent phosphorylation and inhibition of PTEN, which requires CHSA chains and is essential to sustain AKT activation in BRAF V600E-expressing melanoma cells. However, this CHSA-dependent PTEN inhibition is dispensable in cancer cells expressing mutant NRAS or PI3KCA, which directly activate the PI3K-AKT pathway. These results suggest that dietary supplements may exhibit oncogene-dependent pro-tumor effects.

Funding information:
  • NCI NIH HHS - R01 CA140515()
  • NCI NIH HHS - R01 CA174786()
  • NCI NIH HHS - R01 CA183594()
  • Wellcome Trust - 090532(United Kingdom)

As Extracellular Glutamine Levels Decline, Asparagine Becomes an Essential Amino Acid.

  • Pavlova NN
  • Cell Metab.
  • 2018 Feb 6

Literature context: Human: A375 ATCC CRL-1619; RRID:CVCL_0132 Human: SK-UT-1 ATCC HTB-114; CV


Abstract:

When mammalian cells are deprived of glutamine, exogenous asparagine rescues cell survival and growth. Here we report that this rescue results from use of asparagine in protein synthesis. All mammalian cell lines tested lacked cytosolic asparaginase activity and could not utilize asparagine to produce other amino acids or biosynthetic intermediates. Instead, most glutamine-deprived cell lines are capable of sufficient glutamine synthesis to maintain essential amino acid uptake and production of glutamine-dependent biosynthetic precursors, with the exception of asparagine. While experimental introduction of cytosolic asparaginase could enhance the synthesis of glutamine and increase tricarboxylic acid cycle anaplerosis and the synthesis of nucleotide precursors, cytosolic asparaginase suppressed the growth and survival of cells in glutamine-depleted medium in vitro and severely compromised the in vivo growth of tumor xenografts. These results suggest that the lack of asparaginase activity represents an evolutionary adaptation to allow mammalian cells to survive pathophysiologic variations in extracellular glutamine.

Funding information:
  • NCI NIH HHS - P30 CA008748()
  • NIAID NIH HHS - R21 AI091457(United States)

Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma.

  • Yu Y
  • Cancer Cell
  • 2018 Feb 12

Literature context: -old female) ATCC Cat#CRL-1619; RRID:CVCL_0132 Human: melanoma cell lines SK-M


Abstract:

Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases-the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)-disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis. A large subset of established melanoma cell lines and primary human melanoma samples presented with a collective upregulation of related and unrelated H3K9 demethylase activities, whose targeted inhibition restored senescence, even in Braf inhibitor-resistant melanomas, evoked secondary immune effects and controlled tumor growth in vivo.

Funding information:
  • Howard Hughes Medical Institute - MC_U120085811()
  • Intramural NIH HHS - Z99 CA999999(United States)
  • Medical Research Council - R01 CA103846()

Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.

  • Janes MR
  • Cell
  • 2018 Jan 25

Literature context: # CCL-247A375 cell lineATCCCat# CRL-1619LU65 cell lineJapanese Collectio


Abstract:

KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.

Funding information:
  • NCI NIH HHS - R01-CA093678(United States)

A small molecule drug promoting miRNA processing induces alternative splicing of MdmX transcript and rescues p53 activity in human cancer cells overexpressing MdmX protein.

  • Valianatos G
  • PLoS ONE
  • 2017 Oct 3

Literature context: entsThe human cancer cell lines A375, Mel-Juso, Mel-Ho, IPC298, H129


Abstract:

MdmX overexpression contributes to the development of cancer by inhibiting tumor suppressor p53. A switch in the alternative splicing of MdmX transcript, leading to the inclusion of exon 6, has been identified as the primary mechanism responsible for increased MdmX protein levels in human cancers, including melanoma. However, there are no approved drugs, which could translate these new findings into clinical applications. We analyzed the anti-melanoma activity of enoxacin, a fluoroquinolone antibiotic inhibiting the growth of some human cancers in vitro and in vivo by promoting miRNA maturation. We found that enoxacin inhibited the growth and viability of human melanoma cell lines much stronger than a structurally related fluoroquinolone ofloxacin, which only weakly modulates miRNA processing. A microarray analysis identified a set of miRNAs significantly dysregulated in enoxacin-treated A375 melanoma cells. They had the potential to target multiple signaling pathways required for cancer cell growth, among them the RNA splicing. Recent studies showed that interfering with cellular splicing machinery can result in MdmX downregulation in cancer cells. We, therefore, hypothesized that enoxacin could, by modulating miRNAs targeting splicing machinery, activate p53 in melanoma cells overexpressing MdmX. We found that enoxacin and ciprofloxacin, a related fluoroquinolone capable of promoting microRNA processing, but not ofloxacin, strongly activated wild type p53-dependent transcription in A375 melanoma without causing significant DNA damage. On the molecular level, the drugs promoted MdmX exon 6 skipping, leading to a dose-dependent downregulation of MdmX. Not only in melanoma, but also in MCF7 breast carcinoma and A2780 ovarian carcinoma cells overexpressing MdmX. Together, our results suggest that some clinically approved fluoroquinolones could potentially be repurposed as activators of p53 tumor suppressor in cancers overexpressing MdmX oncoprotein and that p53 activation might contribute to the previously reported activity of enoxacin towards human cancer cells.

Funding information:
  • NIGMS NIH HHS - T32 GM007377(United States)

Focal Adhesion- and IGF1R-Dependent Survival and Migratory Pathways Mediate Tumor Resistance to mTORC1/2 Inhibition.

  • Yoon SO
  • Mol. Cell
  • 2017 Aug 3

Literature context: CCRL-2326SKBR3ATCCHTB-30A375ATCCCRL-1619MDA-MB-435ATCCHTB-129SK-MEL-19Dr


Abstract:

Aberrant signaling by the mammalian target of rapamycin (mTOR) contributes to the devastating features of cancer cells. Thus, mTOR is a critical therapeutic target and catalytic inhibitors are being investigated as anti-cancer drugs. Although mTOR inhibitors initially block cell proliferation, cell viability and migration in some cancer cells are quickly restored. Despite sustained inhibition of mTORC1/2 signaling, Akt, a kinase regulating cell survival and migration, regains phosphorylation at its regulatory sites. Mechanistically, mTORC1/2 inhibition promotes reorganization of integrin/focal adhesion kinase-mediated adhesomes, induction of IGFR/IR-dependent PI3K activation, and Akt phosphorylation via an integrin/FAK/IGFR-dependent process. This resistance mechanism contributes to xenograft tumor cell growth, which is prevented with mTOR plus IGFR inhibitors, supporting this combination as a therapeutic approach for cancers.

A CRISPR Resource for Individual, Combinatorial, or Multiplexed Gene Knockout.

  • Erard N
  • Mol. Cell
  • 2017 Jul 20

Literature context: ntal Models: Cell LinesA-375ATCCCRL-1619A-375-Cas9This paperK562-Cas9Gif


Abstract:

We have combined a machine-learning approach with other strategies to optimize knockout efficiency with the CRISPR/Cas9 system. In addition, we have developed a multiplexed sgRNA expression strategy that promotes the functional ablation of single genes and allows for combinatorial targeting. These strategies have been combined to design and construct a genome-wide, sequence-verified, arrayed CRISPR library. This resource allows single-target or combinatorial genetic screens to be carried out at scale in a multiplexed or arrayed format. By conducting parallel loss-of-function screens, we compare our approach to existing sgRNA design and expression strategies.

p27Kip1 promotes invadopodia turnover and invasion through the regulation of the PAK1/Cortactin pathway.

  • Jeannot P
  • Elife
  • 2017 Mar 13

Literature context: 93 (RRID:CVCL_0045), A-375 (RRID:CVCL_0132) and A549 (RRID:CVCL_0023) cell


Abstract:

p27Kip1 (p27) is a cyclin-CDK inhibitor and negative regulator of cell proliferation. p27 also controls other cellular processes including migration and cytoplasmic p27 can act as an oncogene. Furthermore, cytoplasmic p27 promotes invasion and metastasis, in part by promoting epithelial to mesenchymal transition. Herein, we find that p27 promotes cell invasion by binding to and regulating the activity of Cortactin, a critical regulator of invadopodia formation. p27 localizes to invadopodia and limits their number and activity. p27 promotes the interaction of Cortactin with PAK1. In turn, PAK1 promotes invadopodia turnover by phosphorylating Cortactin, and expression of Cortactin mutants for PAK-targeted sites abolishes p27's effect on invadopodia dynamics. Thus, in absence of p27, cells exhibit increased invadopodia stability due to impaired PAK1-Cortactin interaction, but their invasive capacity is reduced compared to wild-type cells. Overall, we find that p27 directly promotes cell invasion by facilitating invadopodia turnover via the Rac1/PAK1/Cortactin pathway.