scholarly journals Activation of PTHrP-cAMP-CREB1 signaling following p53 loss is essential for osteosarcoma initiation and maintenance

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Mannu K Walia ◽  
Patricia MW Ho ◽  
Scott Taylor ◽  
Alvin JM Ng ◽  
Ankita Gupte ◽  
...  
Keyword(s):  
Human Cancer ◽  
Point Mutations ◽  
Therapeutic Targets ◽  
Complete Loss ◽  
Osteoblastic Cells ◽  
Normal Cells ◽  
P53 Pathway ◽  
Common Cancer ◽  
Frequent Event ◽  
Camp Levels

Mutations in the P53 pathway are a hallmark of human cancer. The identification of pathways upon which p53-deficient cells depend could reveal therapeutic targets that may spare normal cells with intact p53. In contrast to P53 point mutations in other cancer, complete loss of P53 is a frequent event in osteosarcoma (OS), the most common cancer of bone. The consequences of p53 loss for osteoblastic cells and OS development are poorly understood. Here we use murine OS models to demonstrate that elevated Pthlh (Pthrp), cAMP levels and signalling via CREB1 are characteristic of both p53-deficient osteoblasts and OS. Normal osteoblasts survive depletion of both PTHrP and CREB1. In contrast, p53-deficient osteoblasts and OS depend upon continuous activation of this pathway and undergo proliferation arrest and apoptosis in the absence of PTHrP or CREB1. Our results identify the PTHrP-cAMP-CREB1 axis as an attractive pathway for therapeutic inhibition in OS.

scholarly journals Tyrosine Phosphorylation Regulates Maturation of Receptor Tyrosine Kinases

2005 ◽  
Vol 25 (9) ◽  
pp. 3690-3703 ◽  
Author(s):  
Dirk-E. Schmidt-Arras ◽  
Annette Böhmer ◽  
Boyka Markova ◽  
Chunaram Choudhary ◽  
Hubert Serve ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Human Cancer ◽  
Point Mutations ◽  
Protein Tyrosine Phosphatases ◽  
Surface Glycoprotein ◽  
Cell Surface Expression ◽  
Wild Type ◽  
Frequent Event

ABSTRACT Constitutive activation of receptor tyrosine kinases (RTKs) is a frequent event in human cancer cells. Activating mutations in Fms-like tyrosine kinase 3 (FLT-3), notably, internal tandem duplications in the juxtamembrane domain (FLT-3 ITD), have been causally linked to acute myeloid leukemia. As we describe here, FLT-3 ITD exists predominantly in an immature, underglycosylated 130-kDa form, whereas wild-type FLT-3 is expressed predominantly as a mature, complex glycosylated 150-kDa molecule. Endogenous FLT-3 ITD, but little wild-type FLT-3, is detectable in the endoplasmic reticulum (ER) compartment. Conversely, cell surface expression of FLT-3 ITD is less efficient than that of wild-type FLT-3. Inhibition of FLT-3 ITD kinase by small molecules, inactivating point mutations, or coexpression with the protein-tyrosine phosphatases (PTPs) SHP-1, PTP1B, and PTP-PEST but not RPTPα promotes complex glycosylation and surface localization. However, PTP coexpression has no effect on the maturation of a surface glycoprotein of vesicular stomatitis virus. The maturation of wild-type FLT-3 is impaired by general PTP inhibition or by suppression of endogenous PTP1B. Enhanced complex formation of FLT-3 ITD with the ER-resident chaperone calnexin indicates that its retention in the ER is related to inefficient folding. The regulation of RTK maturation by tyrosine phosphorylation was observed with other RTKs as well, defines a possible role for ER-resident PTPs, and may be related to the altered signaling quality of constitutively active, transforming RTK mutants.

scholarly journals Crk and CrkL as Therapeutic Targets for Cancer Treatment

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 739
Author(s):  
Taeju Park
Keyword(s):  
Tumor Cell ◽  
Cancer Treatment ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Therapeutic Targets ◽  
Viral Oncoprotein ◽  
Mesenchymal Transition ◽  
Chemotherapy Drugs ◽  
Cell Functions

Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis. Conversely, overexpression of tumor cells with Crk or CrkL enhances tumor cell functions. Therefore, Crk and CrkL have been proposed as therapeutic targets for cancer treatment. However, it is unclear whether Crk and CrkL make distinct or overlapping contributions to tumor cell functions in various cancer types because Crk or CrkL have been examined independently in most studies. Two recent studies using colorectal cancer and glioblastoma cells clearly demonstrated that Crk and CrkL need to be ablated individually and combined to understand distinct and overlapping roles of the two proteins in cancer. A comprehensive understanding of individual and overlapping roles of Crk and CrkL in tumor cell functions is necessary to develop effective therapeutic strategies. This review systematically discusses crucial functions of Crk and CrkL in tumor cell functions and provides new perspectives on targeting Crk and CrkL in cancer therapy.

scholarly journals FIREVAT: finding reliable variants without artifacts in human cancer samples using etiologically relevant mutational signatures

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyunbin Kim ◽  
Andy Jinseok Lee ◽  
Jongkeun Lee ◽  
Hyonho Chun ◽  
Young Seok Ju ◽  
...  
Keyword(s):  
Data Storage ◽  
Human Cancer ◽  
Point Mutations ◽  
Variant Calling ◽  
Human Tumor ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Precision Oncology ◽  
Mutational Signatures ◽  
Accurate Identification

Abstract Background Accurate identification of real somatic variants is a primary part of cancer genome studies and precision oncology. However, artifacts introduced in various steps of sequencing obfuscate confidence in variant calling. Current computational approaches to variant filtering involve intensive interrogation of Binary Alignment Map (BAM) files and require massive computing power, data storage, and manual labor. Recently, mutational signatures associated with sequencing artifacts have been extracted by the Pan-cancer Analysis of Whole Genomes (PCAWG) study. These spectrums can be used to evaluate refinement quality of a given set of somatic mutations. Results Here we introduce a novel variant refinement software, FIREVAT (FInding REliable Variants without ArTifacts), which uses known spectrums of sequencing artifacts extracted from one of the largest publicly available catalogs of human tumor samples. FIREVAT performs a quick and efficient variant refinement that accurately removes artifacts and greatly improves the precision and specificity of somatic calls. We validated FIREVAT refinement performance using orthogonal sequencing datasets totaling 384 tumor samples with respect to ground truth. Our novel method achieved the highest level of performance compared to existing filtering approaches. Application of FIREVAT on additional 308 The Cancer Genome Atlas (TCGA) samples demonstrated that FIREVAT refinement leads to identification of more biologically and clinically relevant mutational signatures as well as enrichment of sequence contexts associated with experimental errors. FIREVAT only requires a Variant Call Format file (VCF) and generates a comprehensive report of the variant refinement processes and outcomes for the user. Conclusions In summary, FIREVAT facilitates a novel refinement strategy using mutational signatures to distinguish artifactual point mutations called in human cancer samples. We anticipate that FIREVAT results will further contribute to precision oncology efforts that rely on accurate identification of variants, especially in the context of analyzing mutational signatures that bear prognostic and therapeutic significance. FIREVAT is freely available at https://github.com/cgab-ncc/FIREVAT

scholarly journals Current understanding of extrachromosomal circular DNA in cancer pathogenesis and therapeutic resistance

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Yuanliang Yan ◽  
Guijie Guo ◽  
Jinzhou Huang ◽  
Ming Gao ◽  
Qian Zhu ◽  
...  
Keyword(s):  
Human Cancer ◽  
Current Understanding ◽  
Therapeutic Resistance ◽  
Testing Strategy ◽  
Circular Dna ◽  
Human Cancer Cells ◽  
Cancer Pathogenesis ◽  
Frequent Event ◽  
Evolutionary Advantage ◽  
Tumor Types

Abstract Extrachromosomal circular DNA was recently found to be particularly abundant in multiple human cancer cells, although its frequency varies among different tumor types. Elevated levels of extrachromosomal circular DNA have been considered an effective biomarker of cancer pathogenesis. Multiple reports have demonstrated that the amplification of oncogenes and therapeutic resistance genes located on extrachromosomal DNA is a frequent event that drives intratumoral genetic heterogeneity and provides a potential evolutionary advantage. This review highlights the current understanding of the extrachromosomal circular DNA present in the tissues and circulation of patients with advanced cancers and provides a detailed discussion of their substantial roles in tumor regulation. Confirming the presence of cancer-related extrachromosomal circular DNA would provide a putative testing strategy for the precision diagnosis and treatment of human malignancies in clinical practice.

scholarly journals N-ω-chloroacetyl-l-ornithine, a new competitive inhibitor of ornithine decarboxylase, induces selective growth inhibition and cytotoxicity on human cancer cells versus normal cells

2014 ◽  
Vol 30 (3) ◽  
pp. 345-353 ◽  
Author(s):  
Miriam Marlene Medina-Enríquez ◽  
Verónica Alcántara-Farfán ◽  
Leopoldo Aguilar-Faisal ◽  
José Guadalupe Trujillo-Ferrara ◽  
Lorena Rodríguez-Páez ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cancer Cells ◽  
Ornithine Decarboxylase ◽  
Human Cancer ◽  
Competitive Inhibitor ◽  
Selective Growth ◽  
Normal Cells ◽  
Human Cancer Cells

scholarly journals Immortalization of Different Breast Epithelial Cell Types Results in Distinct Mitochondrial Mutagenesis

2019 ◽  
Vol 20 (11) ◽  
pp. 2813
Author(s):  
Sujin Kwon ◽  
Susan Kim ◽  
Howard Nebeck ◽  
Eun Ahn
Keyword(s):  
Stem Cell ◽  
Epithelial Cell ◽  
Point Mutations ◽  
Cell Types ◽  
Error Rates ◽  
Breast Epithelial Cell ◽  
Trna Genes ◽  
Normal Cells ◽  
Rare Mutations ◽  
Immortalized Cells

Different phenotypes of normal cells might influence genetic profiles, epigenetic profiles, and tumorigenicities of their transformed derivatives. In this study, we investigate whether the whole mitochondrial genome of immortalized cells can be attributed to the different phenotypes (stem vs. non-stem) of their normal epithelial cell originators. To accurately determine mutations, we employed Duplex Sequencing, which exhibits the lowest error rates among currently-available DNA sequencing methods. Our results indicate that the vast majority of the observed mutations of the whole mitochondrial DNA occur at low-frequency (rare mutations). The most prevalent rare mutation types are C→T/G→A and A→G/T→C transitions. Frequencies and spectra of homoplasmic point mutations are virtually identical between stem cell-derived immortalized (SV1) cells and non-stem cell-derived immortalized (SV22) cells, verifying that both cell types were derived from the same woman. However, frequencies of rare point mutations are significantly lower in SV1 cells (5.79 × 10−5) than in SV22 cells (1.16 × 10−4). The significantly lower frequencies of rare mutations are aligned with a finding of longer average distances to adjacent mutations in SV1 cells than in SV22 cells. Additionally, the predicted pathogenicity for rare mutations in the mitochondrial tRNA genes tends to be lower (by 2.5-fold) in SV1 cells than in SV22 cells. While four known/confirmed pathogenic mt-tRNA mutations (m.5650 G>A, m.5521 G>A, m.5690 A>G, m.1630 A>G) were identified in SV22 cells, no such mutations were observed in SV1 cells. Our findings suggest that the immortalization of normal cells with stem cell features leads to decreased mitochondrial mutagenesis, particularly in RNA gene regions. The mutation spectra and mutations specific to stem cell-derived immortalized cells (vs. non-stem cell derived) have implications in characterizing the heterogeneity of tumors and understanding the role of mitochondrial mutations in the immortalization and transformation of human cells.

scholarly journals Increased levels of superoxide and H2O2 mediate the differential susceptibility of cancer cells versus normal cells to glucose deprivation

2009 ◽  
Vol 418 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Nùkhet Aykin-Burns ◽  
Iman M. Ahmad ◽  
Yueming Zhu ◽  
Larry W. Oberley ◽  
Douglas R. Spitz
Keyword(s):  
Oxidative Stress ◽  
Cancer Cells ◽  
Mammary Epithelial Cells ◽  
Human Cancer ◽  
Differential Susceptibility ◽  
Glucose Deprivation ◽  
Human Colon ◽  
Normal Cells ◽  
Ht29 Cells ◽  
And Oxidative Stress

Cancer cells, relative to normal cells, demonstrate increased sensitivity to glucose-deprivation-induced cytotoxicity. To determine whether oxidative stress mediated by O2•− and hydroperoxides contributed to the differential susceptibility of human epithelial cancer cells to glucose deprivation, the oxidation of DHE (dihydroethidine; for O2•−) and CDCFH2 [5- (and 6-)carboxy-2′,7′-dichlorodihydrofluorescein diacetate; for hydroperoxides] was measured in human colon and breast cancer cells (HT29, HCT116, SW480 and MB231) and compared with that in normal human cells [FHC cells, 33Co cells and HMECs (human mammary epithelial cells)]. Cancer cells showed significant increases in DHE (2–20-fold) and CDCFH2 (1.8–10-fold) oxidation, relative to normal cells, that were more pronounced in the presence of the mitochondrial electron-transport-chain blocker, antimycin A. Furthermore, HCT116 and MB231 cells were more susceptible to glucose-deprivation-induced cytotoxicity and oxidative stress, relative to 33Co cells and HMECs. HT29 cells were also more susceptible to 2DG (2-deoxyglucose)-induced cytotoxicity, relative to FHC cells. Overexpression of manganese SOD (superoxide dismutase) and mitochondrially targeted catalase significantly protected HCT116 and MB231 cells from glucose-deprivation-induced cytotoxicity and oxidative stress and also protected HT29 cells from 2DG-induced cytotoxicity. These results show that cancer cells (relative to normal cells) demonstrate increased steady-state levels of ROS (reactive oxygen species; i.e. O2•− and H2O2) that contribute to differential susceptibility to glucose-deprivation-induced cytotoxicity and oxidative stress. These studies support the hypotheses that cancer cells increase glucose metabolism to compensate for excess metabolic production of ROS and that inhibition of glucose and hydroperoxide metabolism may provide a biochemical target for selectively enhancing cytotoxicity and oxidative stress in human cancer cells.

Identification of Parasporin Genes in Vietnamese Isolates of Bacillus thuringiensis

2008 ◽  
Vol 63 (1-2) ◽  
pp. 139-143 ◽  
Author(s):  
Koichi Yasutake ◽  
Akiko Uemori ◽  
Ngo D. Binh ◽  
Eiichi Mizuki ◽  
Michio Ohba
Keyword(s):  
Bacillus Thuringiensis ◽  
Cancer Cells ◽  
Human Cancer ◽  
Nucleotide Sequence Analysis ◽  
Hep G2 ◽  
Normal Cells ◽  
Proteolytic Activation ◽  
Human Cancer Cells ◽  
Genes Encoding

Four genes encoding parasporins, cytotoxins preferentially killing human cancer cells in vitro, were isolated from four Vietnamese strains of Bacillus thuringiensis. Nucleotide sequence analysis revealed that: (1) three genes fall into the two known classes, ps1Aa and ps1Ab, and (2) another one belongs to ps1Ac, a novel gene class established in this study. Upon proteolytic activation, parasporal protein of the organism with ps1Ac exhibited strong cytocidal activity against human cancer cells, HeLa and Hep G2, but not to non-cancer normal cells, UtSMC and HC.

The p53 pathway and human cancer

2005 ◽  
Vol 92 (11) ◽  
pp. 1331-1332 ◽  
Author(s):  
T. Soussi
Keyword(s):  
Human Cancer ◽  
P53 Pathway
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