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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

(a) Candidate parent compounds selected and evaluated as potential inhibitors of ASPH β-hydroxylase activity were synthesized on the basis of the crystal structure of the catalytic site in the C-terminal region of ASPH using computer assisted drug design. (b) Effects of SMIs on cell viability of FOCUS HCC cells that highly expressed ASPH on the cell surface as a drug screen for biological activity. Note that MO-I-1100 demonstrated a dose dependent effect on cell viability over a range of 0.03 – 3 μM whereas other compounds such as MO-I-100, 300 and 400 for example, showed little, if any, activity.
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Figure 6: (a) Candidate parent compounds selected and evaluated as potential inhibitors of ASPH β-hydroxylase activity were synthesized on the basis of the crystal structure of the catalytic site in the C-terminal region of ASPH using computer assisted drug design. (b) Effects of SMIs on cell viability of FOCUS HCC cells that highly expressed ASPH on the cell surface as a drug screen for biological activity. Note that MO-I-1100 demonstrated a dose dependent effect on cell viability over a range of 0.03 – 3 μM whereas other compounds such as MO-I-100, 300 and 400 for example, showed little, if any, activity.

Mentions: An assay to measure ASPH β-hydroxylase activity had been established as described [11, 12]. This high throughput system was used to screen for potential small molecule inhibitors (SMIs) of β-hydroxylase activity that were synthesized as shown in Fig. 6a. When inhibitors of ASPH β-hydroxylase activity were identified, a functional MTT assay over a range of drug concentrations was performed to assess their effects on cell viability and growth. Examples of positive and negative results among several candidate compounds are depicted in Fig. 6b.


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)

(a) Candidate parent compounds selected and evaluated as potential inhibitors of ASPH β-hydroxylase activity were synthesized on the basis of the crystal structure of the catalytic site in the C-terminal region of ASPH using computer assisted drug design. (b) Effects of SMIs on cell viability of FOCUS HCC cells that highly expressed ASPH on the cell surface as a drug screen for biological activity. Note that MO-I-1100 demonstrated a dose dependent effect on cell viability over a range of 0.03 – 3 μM whereas other compounds such as MO-I-100, 300 and 400 for example, showed little, if any, activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: (a) Candidate parent compounds selected and evaluated as potential inhibitors of ASPH β-hydroxylase activity were synthesized on the basis of the crystal structure of the catalytic site in the C-terminal region of ASPH using computer assisted drug design. (b) Effects of SMIs on cell viability of FOCUS HCC cells that highly expressed ASPH on the cell surface as a drug screen for biological activity. Note that MO-I-1100 demonstrated a dose dependent effect on cell viability over a range of 0.03 – 3 μM whereas other compounds such as MO-I-100, 300 and 400 for example, showed little, if any, activity.
Mentions: An assay to measure ASPH β-hydroxylase activity had been established as described [11, 12]. This high throughput system was used to screen for potential small molecule inhibitors (SMIs) of β-hydroxylase activity that were synthesized as shown in Fig. 6a. When inhibitors of ASPH β-hydroxylase activity were identified, a functional MTT assay over a range of drug concentrations was performed to assess their effects on cell viability and growth. Examples of positive and negative results among several candidate compounds are depicted in Fig. 6b.

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