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NCI-H1299

RRID:CVCL_0060

Organism

Homo sapiens

Comments

Part of: Cancer Cell Line Encyclopedia (CCLE) project. Part of: COSMIC cell lines project. Part of: KuDOS 95 cell line panel. Part of: MD Anderson Cell Lines Project. Doubling time: 30 hours (PubMed=25984343). HLA typing: A*24:02,32:01:01; B*40:01,40:02:01; C*03:03:01,02:02:02 (PubMed=26929325). Microsatellite instability: Stable (MSS) (Sanger). Sequence variation: Heterozygous for NRAS p.Gln61Lys (c.181C>A) (PubMed=12068308; ATCC). Sequence variation: Homozygous for TP53 deletion (PubMed=1565469; ATCC). Omics: Deep exome analysis. Omics: Deep RNAseq analysis. Omics: DNA methylation analysis. Omics: Protein expression by reverse-phase protein arrays. Omics: shRNA library screening. Omics: SNP array analysis. Omics: Transcriptome analysis. Genome ancestry: African=0.33%; Native American=0%; East Asian, North=2.13%; East Asian, South=0%; South Asian=0%; European, North=62.86%; European, South=34.68% (PubMed=30894373). Misspelling: HI299; Occasionally. Derived from metastatic site: Lymph node. DT Created: 04-04-12; Last updated: 05-07-19; Version: 29

Proper Citation

KCLB Cat# 91299, RRID:CVCL_0060

Category

Cancer cell line DT Created: 04-04-12; Last updated: 05-07-19; Version: 29

Sex

DT Created: 04-04-12; Last updated: 05-07-19; Version: 29

Synonyms

H1299, H-1299, NCIH1299 DT Created: 04-04-12, Last updated: 05-07-19, Version: 29

Vendor

KCLB

Cat Num

91299

Cross References

BTO; BTO:0002552 CLO; CLO_0007986 EFO; EFO_0003043 MCCL; MCC:0000352 ArrayExpress; E-MTAB-2706 ArrayExpress; E-MTAB-2770 ArrayExpress; E-MTAB-3610 ATCC; CRL-5803 BCRJ; 0185 BioSample; SAMN03471642 BioSample; SAMN03471739 BioSample; SAMN10988385 CCLE; NCIH1299_LUNG CCRID; 3111C0002000000050 CCRID; 3131C0001000700160 Cell_Model_Passport; SIDM00649 ChEMBL-Cells; CHEMBL3308501 ChEMBL-Targets; CHEMBL612255 Cosmic; 722069 Cosmic; 724831 Cosmic; 877265 Cosmic; 877418 Cosmic; 903585 Cosmic; 961838 Cosmic; 980971 Cosmic; 1004693 Cosmic; 1032443 Cosmic; 1047106 Cosmic; 1066159 Cosmic; 1146875 Cosmic; 1154606 Cosmic; 1175867 Cosmic; 1218870 Cosmic; 1239925 Cosmic; 1609524 Cosmic; 1870264 Cosmic; 1925845 Cosmic; 1995520 Cosmic; 2042873 Cosmic; 2125178 Cosmic; 2630419 Cosmic; 2664126 Cosmic-CLP; 724831 DepMap; ACH-000510 GDSC; 724831 GEO; GSM185871 GEO; GSM206471 GEO; GSM253382 GEO; GSM274743 GEO; GSM274744 GEO; GSM353229 GEO; GSM434266 GEO; GSM784253 GEO; GSM794311 GEO; GSM827467 GEO; GSM844617 GEO; GSM887355 GEO; GSM888433 GEO; GSM1374698 GEO; GSM1374699 GEO; GSM1670165 IARC_TP53; 21537 IARC_TP53; 21722 IGRhCellID; H1299GEO KCLB; 25803 KCLB; 91299 LiGeA; CCLE_300 LINCS_LDP; LCL-1609 Lonza; 796 NCI-DTP; NCI-H1299 PRIDE; PXD003743 TOKU-E; 2592 TOKU-E; 3620 Wikidata; Q5628772 DT Created: 04-04-12; Last updated: 05-07-19; Version: 29

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

  • Kotler E
  • Mol. Cell
  • 2018 Jul 5

Literature context:


Abstract:

The TP53 gene is frequently mutated in human cancer. Research has focused predominantly on six major "hotspot" codons, which account for only ∼30% of cancer-associated p53 mutations. To comprehensively characterize the consequences of the p53 mutation spectrum, we created a synthetically designed library and measured the functional impact of ∼10,000 DNA-binding domain (DBD) p53 variants in human cells in culture and in vivo. Our results highlight the differential outcome of distinct p53 mutations in human patients and elucidate the selective pressure driving p53 conservation throughout evolution. Furthermore, while loss of anti-proliferative functionality largely correlates with the occurrence of cancer-associated p53 mutations, we observe that selective gain-of-function may further favor particular mutants in vivo. Finally, when combined with additional acquired p53 mutations, seemingly neutral TP53 SNPs may modulate phenotypic outcome and, presumably, tumor progression.

Funding information:
  • NIDDK NIH HHS - DK091222-01(United States)

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:


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)

UBE2M Is a Stress-Inducible Dual E2 for Neddylation and Ubiquitylation that Promotes Targeted Degradation of UBE2F.

  • Zhou W
  • Mol. Cell
  • 2018 Jun 21

Literature context:


Abstract:

UBE2M and UBE2F are two family members of neddylation E2 conjugating enzyme that, together with E3s, activate CRLs (Cullin-RING Ligases) by catalyzing cullin neddylation. However, whether and how two E2s cross-talk with each other are largely unknown. Here, we report that UBE2M is a stress-inducible gene subjected to cis-transactivation by HIF-1 and AP1, and MLN4924, a small molecule inhibitor of E1 NEDD8-activating enzyme (NAE), upregulates UBE2M via blocking degradation of HIF-1α and c-JUN. UBE2M is a dual E2 for targeted ubiquitylation and degradation of UBE2F, acting as a neddylation E2 to activate CUL3-Keap1 E3 under physiological conditions but as a ubiquitylation E2 for Parkin-DJ-1 E3 under stressed conditions. UBE2M-induced UBE2F degradation leads to CRL5 inactivation and subsequent NOXA accumulation to suppress the growth of lung cancer cells. Collectively, our study establishes a negative regulatory axis between two neddylation E2s with UBE2M ubiquitylating UBE2F, and two CRLs with CRL3 inactivating CRL5.

Funding information:
  • NCI NIH HHS - R01 CA156744()
  • NCI NIH HHS - R01 CA171277()
  • NCI NIH HHS - R01-CA078461(United States)

SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer.

  • Fang Z
  • Elife
  • 2018 Mar 16

Literature context:


Abstract:

Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here, we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.

Funding information:
  • National Institutes of Health - 2G12MD007595()
  • National Institutes of Health - R01CA095441()
  • National Institutes of Health - R01CA127724()
  • National Institutes of Health - R01CA172468()
  • National Institutes of Health - R21 CA201889()
  • National Institutes of Health - R21CA190775()
  • NCI NIH HHS - CA89194(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:


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)

CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness.

  • Su S
  • Cell
  • 2018 Feb 8

Literature context:


Abstract:

Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.

Funding information:
  • NHLBI NIH HHS - R01 HL064018(United States)

iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding.

  • Ge W
  • Cancer Cell
  • 2017 Nov 13

Literature context:


Abstract:

Reactive oxygen species (ROS) have emerged as important signaling molecules that play crucial roles in carcinogenesis and cytotoxic responses. Nrf2 is the master regulator of ROS balance. Thus, uncovering mechanisms of Nrf2 regulation is important for the development of alternative treatment strategies for cancers. Here, we demonstrate that iASPP, a known p53 inhibitor, lowers ROS independently of p53. Mechanistically, iASPP competes with Nrf2 for Keap1 binding via a DLT motif, leading to decreased Nrf2 ubiquitination and increased Nrf2 accumulation, nuclear translocation, and antioxidative transactivation. This iASPP-Keap1-Nrf2 axis promotes cancer growth and drug resistance both in vitro and in vivo. Thus, iASPP is an antioxidative factor and represents a promising target to improve cancer treatment, regardless of p53 status.

Funding information:
  • NCI NIH HHS - R01CA169200(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:


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)

A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants.

  • Gabrielsen M
  • Mol. Cell
  • 2017 Oct 19

Literature context:


Abstract:

RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site. Surprisingly, the UbV selective for dimeric XIAP formed a dimer to stimulate E3 activity by stabilizing the closed E2∼Ub conformation. We further verified the inhibitory and stimulatory functions of UbVs in cells. Our work provides a general strategy to inhibit or activate RING/U-box E3 ligases and provides a resource for the research community to modulate these enzymes.

Angiopoietin-like 4 Is a Wnt Signaling Antagonist that Promotes LRP6 Turnover.

  • Kirsch N
  • Dev. Cell
  • 2017 Oct 9

Literature context:


Abstract:

Angiopoietin-like 4 (ANGPTL4) is a secreted signaling protein that is implicated in cardiovascular disease, metabolic disorder, and cancer. Outside of its role in lipid metabolism, ANGPTL4 signaling remains poorly understood. Here, we identify ANGPTL4 as a Wnt signaling antagonist that binds to syndecans and forms a ternary complex with the Wnt co-receptor Lipoprotein receptor-related protein 6 (LRP6). This protein complex is internalized via clathrin-mediated endocytosis and degraded in lysosomes, leading to attenuation of Wnt/β-catenin signaling. Angptl4 is expressed in the Spemann organizer of Xenopus embryos and acts as a Wnt antagonist to promote notochord formation and prevent muscle differentiation. This unexpected function of ANGPTL4 invites re-interpretation of its diverse physiological effects in light of Wnt signaling and may open therapeutic avenues for human disease.

Ccdc3: A New P63 Target Involved in Regulation Of Liver Lipid Metabolism.

  • Liao W
  • Sci Rep
  • 2017 Aug 21

Literature context:


Abstract:

TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.

Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition.

  • Muir A
  • Elife
  • 2017 Aug 15

Literature context:


Abstract:

Many mammalian cancer cell lines depend on glutamine as a major tri-carboxylic acid (TCA) cycle anaplerotic substrate to support proliferation. However, some cell lines that depend on glutamine anaplerosis in culture rely less on glutamine catabolism to proliferate in vivo. We sought to understand the environmental differences that cause differential dependence on glutamine for anaplerosis. We find that cells cultured in adult bovine serum, which better reflects nutrients available to cells in vivo, exhibit decreased glutamine catabolism and reduced reliance on glutamine anaplerosis compared to cells cultured in standard tissue culture conditions. We find that levels of a single nutrient, cystine, accounts for the differential dependence on glutamine in these different environmental contexts. Further, we show that cystine levels dictate glutamine dependence via the cystine/glutamate antiporter xCT/SLC7A11. Thus, xCT/SLC7A11 expression, in conjunction with environmental cystine, is necessary and sufficient to increase glutamine catabolism, defining important determinants of glutamine anaplerosis and glutaminase dependence in cancer.

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy.

  • Li X
  • Mol. Cell
  • 2017 Jun 1

Literature context:


Abstract:

Overcoming metabolic stress is a critical step in tumor growth. Acetyl coenzyme A (acetyl-CoA) generated from glucose and acetate uptake is important for histone acetylation and gene expression. However, how acetyl-CoA is produced under nutritional stress is unclear. We demonstrate here that glucose deprivation results in AMP-activated protein kinase (AMPK)-mediated acetyl-CoA synthetase 2 (ACSS2) phosphorylation at S659, which exposed the nuclear localization signal of ACSS2 for importin α5 binding and nuclear translocation. In the nucleus, ACSS2 binds to transcription factor EB and translocates to lysosomal and autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and promote lysosomal biogenesis, autophagy, cell survival, and brain tumorigenesis. In addition, ACSS2 S659 phosphorylation positively correlates with AMPK activity in glioma specimens and grades of glioma malignancy. These results underscore the significance of nuclear ACSS2-mediated histone acetylation in maintaining cell homeostasis and tumor development.

Funding information:
  • NCI NIH HHS - R01 CA109035()
  • NCI NIH HHS - R01 CA169603()
  • NCI NIH HHS - R01 CA204996()
  • NINDS NIH HHS - R01 NS094615()

Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication.

  • Foskolou IP
  • Mol. Cell
  • 2017 Apr 20

Literature context:


Abstract:

Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here, we show that the RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favored over RRM1/RRM2 in order to preserve ongoing replication and avoid the accumulation of DNA damage. We found two distinct mechanisms by which RRM2B maintains hypoxic activity and identified responsible residues in RRM2B. The importance of RRM2B in the response to tumor hypoxia is further illustrated by correlation of its expression with a hypoxic signature in patient samples and its roles in tumor growth and radioresistance. Our data provide mechanistic insight into RNR biology, highlighting RRM2B as a hypoxic-specific, anti-cancer therapeutic target.

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

  • Liao P
  • Elife
  • 2017 Mar 31

Literature context:


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.

Decoupling global biases and local interactions between cell biological variables.

  • Zaritsky A
  • Elife
  • 2017 Mar 13

Literature context:


Abstract:

Analysis of coupled variables is a core concept of cell biological inference, with co-localization of two molecules as a proxy for protein interaction being a ubiquitous example. However, external effectors may influence the observed co-localization independently from the local interaction of two proteins. Such global bias, although biologically meaningful, is often neglected when interpreting co-localization. Here, we describe DeBias, a computational method to quantify and decouple global bias from local interactions between variables by modeling the observed co-localization as the cumulative contribution of a global and a local component. We showcase four applications of DeBias in different areas of cell biology, and demonstrate that the global bias encapsulates fundamental mechanistic insight into cellular behavior. The DeBias software package is freely accessible online via a web-server at https://debias.biohpc.swmed.edu.

Funding information:
  • NIGMS NIH HHS - P01 GM096971()
  • NIGMS NIH HHS - P01 GM103723()
  • NIGMS NIH HHS - R01 GM073165()

MK-8776, a novel chk1 kinase inhibitor, radiosensitizes p53-defective human tumor cells.

  • Bridges KA
  • Oncotarget
  • 2016 Nov 1

Literature context:


Abstract:

Radiotherapy is commonly used to treat a variety of solid tumors but improvements in the therapeutic ratio are sorely needed. The aim of this study was to assess the Chk1 kinase inhibitor, MK-8776, for its ability to radiosensitize human tumor cells. Cells derived from NSCLC and HNSCC cancers were tested for radiosensitization by MK-8776. The ability of MK-8776 to abrogate the radiation-induced G2 block was determined using flow cytometry. Effects on repair of radiation-induced DNA double strand breaks (DSBs) were determined on the basis of rad51, γ-H2AX and 53BP1 foci. Clonogenic survival analyses indicated that MK-8776 radiosensitized p53-defective tumor cells but not lines with wild-type p53. Abrogation of the G2 block was evident in both p53-defective cells and p53 wild-type lines indicating no correlation with radiosensitization. However, only p53-defective cells entered mitosis harboring unrepaired DSBs. MK-8776 appeared to inhibit repair of radiation-induced DSBs at early times after irradiation. A comparison of MK-8776 to the wee1 inhibitor, MK-1775, suggested both similarities and differences in their activities. In conclusion, MK-8776 radiosensitizes tumor cells by mechanisms that include abrogation of the G2 block and inhibition of DSB repair. Our findings support the clinical evaluation of MK-8776 in combination with radiation.

TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions.

  • Shirole NH
  • Elife
  • 2016 Oct 19

Literature context:


Abstract:

TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles. Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis. Functionally and molecularly, these p53 mutants resemble the naturally occurring alternative p53 splice variant, p53-psi. Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD). Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.

Funding information:
  • NEI NIH HHS - R01 EY006069(United States)

Inactivation of oncogenic cAMP-specific phosphodiesterase 4D by miR-139-5p in response to p53 activation.

  • Cao B
  • Elife
  • 2016 Jul 7

Literature context:


Abstract:

Increasing evidence highlights the important roles of microRNAs in mediating p53's tumor suppression functions. Here, we report miR-139-5p as another new p53 microRNA target. p53 induced the transcription of miR-139-5p, which in turn suppressed the protein levels of phosphodiesterase 4D (PDE4D), an oncogenic protein involved in multiple tumor promoting processes. Knockdown of p53 reversed these effects. Also, overexpression of miR-139-5p decreased PDE4D levels and increased cellular cAMP levels, leading to BIM-mediated cell growth arrest. Furthermore, our analysis of human colorectal tumor specimens revealed significant inverse correlation between the expression of miR-139-5p and that of PDE4D. Finally, overexpression of miR-139-5p suppressed the growth of xenograft tumors, accompanied by decrease in PDE4D and increase in BIM. These results demonstrate that p53 inactivates oncogenic PDE4D by inducing the expression of miR-139-5p.