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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

Stable overexpression of ASPH in MIA PaCa2 cells promotes cell proliferation(a), wound healing (b), migration (c), invasion (d), and colony formation (e) as indices of changes in the malignant phenotype. ASPH overexpression also enhances the expression of activated Notch1, JAG2, and Notch signaling downstream target genes including HES1, HEY1, EpCAM, CD44, c-Myc, MMP2/9, cyclin D3 and PCNA as shown in Western blot analysis (f). *p<0.05; **p<0.01; ***p<0.001.
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Figure 2: Stable overexpression of ASPH in MIA PaCa2 cells promotes cell proliferation(a), wound healing (b), migration (c), invasion (d), and colony formation (e) as indices of changes in the malignant phenotype. ASPH overexpression also enhances the expression of activated Notch1, JAG2, and Notch signaling downstream target genes including HES1, HEY1, EpCAM, CD44, c-Myc, MMP2/9, cyclin D3 and PCNA as shown in Western blot analysis (f). *p<0.05; **p<0.01; ***p<0.001.

Mentions: Figure 2 panel a-e demonstrate the biological effects of ASPH overexpression on the PC cell phenotype on MIA PaCa2 as measured by proliferation, migration, invasion, as well as colony formation as an index of malignant transformation. Similar findings were evident with stable ASPH transfected Capan-1 cells (data not shown). This aggressive malignant phenotype was significantly attenuated by specific shRNAs “knockdown” of ASPH in AsPC-1 cells with high endogenous levels as demonstrated by a reduction in proliferation, migration, invasion and colony formation (Fig. 3, panel a-e).


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)

Stable overexpression of ASPH in MIA PaCa2 cells promotes cell proliferation(a), wound healing (b), migration (c), invasion (d), and colony formation (e) as indices of changes in the malignant phenotype. ASPH overexpression also enhances the expression of activated Notch1, JAG2, and Notch signaling downstream target genes including HES1, HEY1, EpCAM, CD44, c-Myc, MMP2/9, cyclin D3 and PCNA as shown in Western blot analysis (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 2: Stable overexpression of ASPH in MIA PaCa2 cells promotes cell proliferation(a), wound healing (b), migration (c), invasion (d), and colony formation (e) as indices of changes in the malignant phenotype. ASPH overexpression also enhances the expression of activated Notch1, JAG2, and Notch signaling downstream target genes including HES1, HEY1, EpCAM, CD44, c-Myc, MMP2/9, cyclin D3 and PCNA as shown in Western blot analysis (f). *p<0.05; **p<0.01; ***p<0.001.
Mentions: Figure 2 panel a-e demonstrate the biological effects of ASPH overexpression on the PC cell phenotype on MIA PaCa2 as measured by proliferation, migration, invasion, as well as colony formation as an index of malignant transformation. Similar findings were evident with stable ASPH transfected Capan-1 cells (data not shown). This aggressive malignant phenotype was significantly attenuated by specific shRNAs “knockdown” of ASPH in AsPC-1 cells with high endogenous levels as demonstrated by a reduction in proliferation, migration, invasion and colony formation (Fig. 3, panel a-e).

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