Constitutive autotaxin transcription by Nmyc‐amplified and non‐amplified neuroblastoma cells is regulated by a novel AP‐1 and SP‐mediated mechanism and abrogated by curcumin

Farina, Antonietta R.; Cappabianca, Lucia; Ruggeri, Pierdomenico; Ianni, Natalia Di; Ragone, Marzia; Merolle, Stefania; Sano, Kimihiko; Stracke, Mary L.; Horowitz, Jordan M.; Gulino, Alberto; Mackay, Andrew R.

doi:10.1016/j.febslet.2012.08.026

Cited by 23 publications

(16 citation statements)

References 37 publications

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“…L1 cell adhesion molecule (L1CAM) was the fourth most abundant protein in SK-N-BE2 (72-fold highly abundant compared to SH-SY5Y) and is known to be an indicator for developing neuronal cells in more mature stages of neuroblastoma [ 26 ]. The motility, angiogenesis and metastasis-stimulating factor Autotaxin (ENPP2) [ 27 ], was 65-fold enriched in SK-N-BE2. Similarly, dopa decarboxylase (DDC) was 28-fold highly abundant in SK-N-BE2.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

et al. 2015

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Neuroblastoma arises from the sympathetic nervous system and accounts for 15% of childhood cancer mortality. Amplification of the oncogene N-Myc is reported to occur in more than 20% of patients. While N-Myc amplification status strongly correlates with higher tumour aggression and resistance to treatment, the role of N-Myc in the aggressive progression of the disease is poorly understood. N-Myc being a transcription factor can modulate the secretion of key proteins that may play a pivotal role in tumorigenesis. Characterising the soluble secreted proteins or secretome will aid in understanding their role in the tumour microenvironment, such as promoting cancer cell invasion and resistance to treatment. The aim of this study is to characterise the secretome of human malignant neuroblastoma SK-N-BE2 (N-Myc amplified, more aggressive) and SH-SY5Y (N-Myc non-amplified, less aggressive) cells. Conditioned media from SK-N-BE2 and SH-SY5Y cell lines were subjected to proteomics analysis. We report a catalogue of 894 proteins identified in the secretome isolated from the two neuroblastoma cell lines, SK-N-BE2 and SH-SY5Y. Functional enrichment analysis using FunRich software identified enhanced secretion of proteins implicated in cysteine peptidase activity in the aggressive N-Myc amplified SK-N-BE2 secretome compared to the less tumorigenic SH-SY5Y cells. Protein-protein interaction-based network analysis highlighted the enrichment of cathepsin and epithelial-to-mesenchymal transition sub-networks. For the first time, inhibition of cathepsins by inhibitors sensitized the resistant SK-N-BE2 cells to doxorubicin as well as decreased its migratory potential. The dataset of secretome proteins of N-Myc amplified (more aggressive) and non-amplified (less aggressive) neuroblastoma cells represent the first inventory of neuroblastoma secretome. The study also highlights the prominent role of cathepsins in the N-Myc amplified neuroblastoma pathogenesis. As N-Myc amplification correlates with aggressive neuroblastoma and chemotherapy-based treatment failure, co-treatment with cathepsin inhibitors might be a better avenue for disease management.

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Section: Resultsmentioning

confidence: 99%

Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

et al. 2015

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“…These studies have shown that the ENPP2 gene is devoid of typical TATA or CAAT motifs at the 5 ′ region but contains putative binding sites for at least four transcription factors, including Max1, HNF-3B, AP, and Sp1, and a probable octamer binding locus in intron 2. In addition, studies in neuroblastoma cells showed that AP-1 and Sp3 transcription factors control ATX expression by binding to CRE/AP-1-like and GAbox elements at the upstream regulatory regions ( 41 ). A more recent study suggests that ATX gene transcription GTP 5 ′ ␤ -phosphates, hydrolyzes the AMP group from the NAD molecule, and functions as an ATP pyrophosphatase by removing the entire pyrophosphate group from nucleoside phosphate molecules ( 3 ).…”

Section: Transcriptional Control and Secretionmentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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“…Previous work has demonstrated that over‐expression of v‐Jun induces autotaxin in chick embryo fibroblasts . c‐Jun and JunD bind to a CRE/AP1‐like site in the autotaxin promoter and enhance promoter activity, suggesting that autotaxin may be a direct c‐Jun target .…”

Section: Resultsmentioning

confidence: 99%

c‐Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas

Sioletic

Czaplinski

et al. 2014

The Journal of Pathology

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Genomic amplification of the c-Jun proto-oncogene has been identified in ~30% of dedifferentiated liposarcomas (DDLPS), but the functional contribution of c-Jun to the progression of DDLPS remains poorly understood. In previous work, we showed that knockdown of c-Jun by RNA interference impaired the in vitro proliferation and in vivo growth of a DDLPS cell line (LP6) with genomic amplification of the c-Jun locus. Here, we use gene expression analysis and functional studies in a broad panel of cell lines to further define the role of c-Jun in DDLPS and other soft tissue sarcomas. We show that c-Jun knockdown impairs transition through the G1 phase of the cell cycle in multiple DDLPS cell lines. We also find that high levels of c-Jun expression are both necessary and sufficient to promote DDLPS cell migration and invasion in vitro. Our data suggest that high levels of c-Jun enhance motility in part by driving the expression of ENPP2/Autotaxin. c-Jun overexpression has minimal effects on in vitro proliferation, but substantially enhances the in vivo growth of weakly tumorigenic DDLPS cell lines. Finally, we provide evidence that c-Jun genomic amplification and overexpression may have similar functional consequences in other types of soft tissue sarcoma. Our data suggest a model in which relatively low levels of c-Jun are sufficient for in vitro proliferation, but high levels of c-Jun enhance invasiveness and capacity for in vivo tumor growth. These observations provide an explanation for the selective advantage provided by c-Jun genomic amplification in vivo and suggest that sarcomas with elevated c-Jun levels are likely to have a particularly high malignant potential.

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Constitutive autotaxin transcription by Nmyc‐amplified and non‐amplified neuroblastoma cells is regulated by a novel AP‐1 and SP‐mediated mechanism and abrogated by curcumin

Cited by 23 publications

References 37 publications

Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

Inhibition of cathepsin proteases attenuates migration and sensitizes aggressive N-Myc amplified human neuroblastoma cells to doxorubicin

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

c‐Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas

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