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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

The γ-secretase inhibitor DAPT (at a concentration of 10 μM) reversed the aggressive malignant phenotype exhibited by ASPH overexpression in MIA PaCa2 cellsDAPT attenuated ASPH induced (a) cell proliferation, (b) migration and (c) colony formation through inhibition of Notch1 ICN signaling. A SMI (MO-I-1100) exerted inhibitory effects on the PC phenotype induced by endogenous high-level of ASPH expression. A significant reduction in (d, e) migration and (f, g) invasion was observed in HPAFII and AsPC-1 PC cells with high endogenous levels of ASPH (Fig. 1) treated with MO-I-1100 at 5 μM. *p<0.05; **p<0.01; ***p<0.001 when compared with control.
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Figure 8: The γ-secretase inhibitor DAPT (at a concentration of 10 μM) reversed the aggressive malignant phenotype exhibited by ASPH overexpression in MIA PaCa2 cellsDAPT attenuated ASPH induced (a) cell proliferation, (b) migration and (c) colony formation through inhibition of Notch1 ICN signaling. A SMI (MO-I-1100) exerted inhibitory effects on the PC phenotype induced by endogenous high-level of ASPH expression. A significant reduction in (d, e) migration and (f, g) invasion was observed in HPAFII and AsPC-1 PC cells with high endogenous levels of ASPH (Fig. 1) treated with MO-I-1100 at 5 μM. *p<0.05; **p<0.01; ***p<0.001 when compared with control.

Mentions: To further link the association between ASPH overexpression and Notch activation, we treated MIA PaCa2 cells with a γ-secretase inhibitor (DAPT) as shown in Fig. 8. Treatment reduced PC proliferation, migration and colony formation. Similar results were obtained with HPAFII and AsPC-1 PC cells which have high endogenous levels of ASPH indicating that enhanced migration and invasion could be inhibited by MO-I-1100, a SMI of ASPH β-hydroxylase activity in vitro under these conditions as well (Fig. 8d-g).


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)

The γ-secretase inhibitor DAPT (at a concentration of 10 μM) reversed the aggressive malignant phenotype exhibited by ASPH overexpression in MIA PaCa2 cellsDAPT attenuated ASPH induced (a) cell proliferation, (b) migration and (c) colony formation through inhibition of Notch1 ICN signaling. A SMI (MO-I-1100) exerted inhibitory effects on the PC phenotype induced by endogenous high-level of ASPH expression. A significant reduction in (d, e) migration and (f, g) invasion was observed in HPAFII and AsPC-1 PC cells with high endogenous levels of ASPH (Fig. 1) treated with MO-I-1100 at 5 μM. *p<0.05; **p<0.01; ***p<0.001 when compared with control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: The γ-secretase inhibitor DAPT (at a concentration of 10 μM) reversed the aggressive malignant phenotype exhibited by ASPH overexpression in MIA PaCa2 cellsDAPT attenuated ASPH induced (a) cell proliferation, (b) migration and (c) colony formation through inhibition of Notch1 ICN signaling. A SMI (MO-I-1100) exerted inhibitory effects on the PC phenotype induced by endogenous high-level of ASPH expression. A significant reduction in (d, e) migration and (f, g) invasion was observed in HPAFII and AsPC-1 PC cells with high endogenous levels of ASPH (Fig. 1) treated with MO-I-1100 at 5 μM. *p<0.05; **p<0.01; ***p<0.001 when compared with control.
Mentions: To further link the association between ASPH overexpression and Notch activation, we treated MIA PaCa2 cells with a γ-secretase inhibitor (DAPT) as shown in Fig. 8. Treatment reduced PC proliferation, migration and colony formation. Similar results were obtained with HPAFII and AsPC-1 PC cells which have high endogenous levels of ASPH indicating that enhanced migration and invasion could be inhibited by MO-I-1100, a SMI of ASPH β-hydroxylase activity in vitro under these conditions as well (Fig. 8d-g).

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