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Aspartate β-Hydroxylase expression promotes a malignant pancreatic cellular phenotype.

Dong X, Lin Q, Aihara A, Li Y, Huang CK, Chung W, Tang Q, Chen X, Carlson R, Nadolny C, Gabriel G, Olsen M, Wands JR - Oncotarget (2015)

Bottom Line: The transforming properties of ASPH depend on enzymatic activity.ASPH links PC growth factor signaling cascades to Notch activation.A small molecule inhibitor of β-hydroxylase activity was developed and found to reduce PC growth by downregulating the Notch signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA.

ABSTRACT
Pancreatic cancer (PC) is one of the leading causes of cancer related deaths due to aggressive progression and metastatic spread. Aspartate β-hydroxylase (ASPH), a cell surface protein that catalyzes the hydroxylation of epidermal growth factor (EGF)-like repeats in Notch receptors and ligands, is highly overexpressed in PC. ASPH upregulation confers a malignant phenotype characterized by enhanced cell proliferation, migration, invasion and colony formation in vitro as well as PC tumor growth in vivo. The transforming properties of ASPH depend on enzymatic activity. ASPH links PC growth factor signaling cascades to Notch activation. A small molecule inhibitor of β-hydroxylase activity was developed and found to reduce PC growth by downregulating the Notch signaling pathway. These findings demonstrate the critical involvement of ASPH in PC growth and progression, provide new insight into the molecular mechanisms leading to tumor development and growth and have important therapeutic implications.

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Related in: MedlinePlus

Effect of SMI MO-I-1100 on the PC phenotype induced by exogenous or endogenous high-level of WT-ASPH expressionMIA PaCa2 cells stably transfected with empty vector or the “wild type” ASPH construct via lentiviral transfection depicted in Fig. 2. The inhibitory effects of MO-I-1100 on (a) proliferation, (b) migration, (c) invasion, and (d) colony formation of MIA PaCa2 cells were observed. There is a significant reduction in the expression of Notch1 ICN, JAG2, as well as downstream responsive genes HES1, HEY1, EpCAM, CD44, c-Myc, MMP2/9, cyclin D3 and PCNA induced by MO-I-1100 compared to the DMSO treatment (e and f). *p<0.05; **p<0.01; ***p<0.001.
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Figure 7: Effect of SMI MO-I-1100 on the PC phenotype induced by exogenous or endogenous high-level of WT-ASPH expressionMIA PaCa2 cells stably transfected with empty vector or the “wild type” ASPH construct via lentiviral transfection depicted in Fig. 2. The inhibitory effects of MO-I-1100 on (a) proliferation, (b) migration, (c) invasion, and (d) colony formation of MIA PaCa2 cells were observed. There is a significant reduction in the expression of Notch1 ICN, JAG2, as well as downstream responsive genes HES1, HEY1, EpCAM, CD44, c-Myc, MMP2/9, cyclin D3 and PCNA induced by MO-I-1100 compared to the DMSO treatment (e and f). *p<0.05; **p<0.01; ***p<0.001.

Mentions: The biological effects of reduced ASPH enzymatic activity on generation of a malignant phenotype was evaluated. Figure 7 demonstrates the inhibitory effects of MO-I-1100 on ASPH induced proliferation, migration, invasion and colony formation, as well as Notch signaling activation in MIA PaCa2 cells with high expression of WT-ASPH.


Aspartate β-Hydroxylase expression promotes a malignant pancreatic cellular phenotype.

Dong X, Lin Q, Aihara A, Li Y, Huang CK, Chung W, Tang Q, Chen X, Carlson R, Nadolny C, Gabriel G, Olsen M, Wands JR - Oncotarget (2015)

Effect of SMI MO-I-1100 on the PC phenotype induced by exogenous or endogenous high-level of WT-ASPH expressionMIA PaCa2 cells stably transfected with empty vector or the “wild type” ASPH construct via lentiviral transfection depicted in Fig. 2. The inhibitory effects of MO-I-1100 on (a) proliferation, (b) migration, (c) invasion, and (d) colony formation of MIA PaCa2 cells were observed. There is a significant reduction in the expression of Notch1 ICN, JAG2, as well as downstream responsive genes HES1, HEY1, EpCAM, CD44, c-Myc, MMP2/9, cyclin D3 and PCNA induced by MO-I-1100 compared to the DMSO treatment (e and f). *p<0.05; **p<0.01; ***p<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359229&req=5

Figure 7: Effect of SMI MO-I-1100 on the PC phenotype induced by exogenous or endogenous high-level of WT-ASPH expressionMIA PaCa2 cells stably transfected with empty vector or the “wild type” ASPH construct via lentiviral transfection depicted in Fig. 2. The inhibitory effects of MO-I-1100 on (a) proliferation, (b) migration, (c) invasion, and (d) colony formation of MIA PaCa2 cells were observed. There is a significant reduction in the expression of Notch1 ICN, JAG2, as well as downstream responsive genes HES1, HEY1, EpCAM, CD44, c-Myc, MMP2/9, cyclin D3 and PCNA induced by MO-I-1100 compared to the DMSO treatment (e and f). *p<0.05; **p<0.01; ***p<0.001.
Mentions: The biological effects of reduced ASPH enzymatic activity on generation of a malignant phenotype was evaluated. Figure 7 demonstrates the inhibitory effects of MO-I-1100 on ASPH induced proliferation, migration, invasion and colony formation, as well as Notch signaling activation in MIA PaCa2 cells with high expression of WT-ASPH.

Bottom Line: The transforming properties of ASPH depend on enzymatic activity.ASPH links PC growth factor signaling cascades to Notch activation.A small molecule inhibitor of β-hydroxylase activity was developed and found to reduce PC growth by downregulating the Notch signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA.

ABSTRACT
Pancreatic cancer (PC) is one of the leading causes of cancer related deaths due to aggressive progression and metastatic spread. Aspartate β-hydroxylase (ASPH), a cell surface protein that catalyzes the hydroxylation of epidermal growth factor (EGF)-like repeats in Notch receptors and ligands, is highly overexpressed in PC. ASPH upregulation confers a malignant phenotype characterized by enhanced cell proliferation, migration, invasion and colony formation in vitro as well as PC tumor growth in vivo. The transforming properties of ASPH depend on enzymatic activity. ASPH links PC growth factor signaling cascades to Notch activation. A small molecule inhibitor of β-hydroxylase activity was developed and found to reduce PC growth by downregulating the Notch signaling pathway. These findings demonstrate the critical involvement of ASPH in PC growth and progression, provide new insight into the molecular mechanisms leading to tumor development and growth and have important therapeutic implications.

Show MeSH
Related in: MedlinePlus