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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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Hypothesis of how ASPH may be involved in the pathogenesis of PC progression through Notch activation [6]The structure of ASPH molecule consists of cytoplasmic (green), transmembrane (purple), luminal region (blue) and catalytic domain (red), which contains the catalytic site (M670HPGTH675). (a) In the presence of β-hydroxylase activity of ASPH, binding of the JAG ligand (green) on one cell to the Notch receptor (purple) on another cell results in two proteolytic cleavages of the receptor. The ADAM10 or TACE (TNF-α-converting enzyme; ADAM17) metalloprotease (black) catalyzes the S2 cleavage and generates a substrate for S3 cleavage by the γ-secretase complex (red). This proteolytic processing mediates release of the Notch intracellular domain (NICD), which enters the nucleus and interacts with the DNA-binding CSL (CBF1, Su(H) and LAG-1) protein. The co-activator Mastermind (Mam) and other transcription factors are recruited to the CSL complex, whereas co-repressors (Co-R) are released. Thus, the Notch signaling is on and the downstream target genes are expressed: CD44 and EpCAM are markers for cancer stem cells; PCNA, cyclin D3, c-Myc, MMP2/9, HES1 and HEY1 are involved in cell proliferation, migration, invasion, tumor growth and metastasis in PC. (b) SMIs block the catalytic site of ASPH, which leads to loss of β-hydroxylase activity and failure of JAG2 binding to Notch1. Thus, Notch signaling is off and its oncogenic effector is inhibited in PC.
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Figure 10: Hypothesis of how ASPH may be involved in the pathogenesis of PC progression through Notch activation [6]The structure of ASPH molecule consists of cytoplasmic (green), transmembrane (purple), luminal region (blue) and catalytic domain (red), which contains the catalytic site (M670HPGTH675). (a) In the presence of β-hydroxylase activity of ASPH, binding of the JAG ligand (green) on one cell to the Notch receptor (purple) on another cell results in two proteolytic cleavages of the receptor. The ADAM10 or TACE (TNF-α-converting enzyme; ADAM17) metalloprotease (black) catalyzes the S2 cleavage and generates a substrate for S3 cleavage by the γ-secretase complex (red). This proteolytic processing mediates release of the Notch intracellular domain (NICD), which enters the nucleus and interacts with the DNA-binding CSL (CBF1, Su(H) and LAG-1) protein. The co-activator Mastermind (Mam) and other transcription factors are recruited to the CSL complex, whereas co-repressors (Co-R) are released. Thus, the Notch signaling is on and the downstream target genes are expressed: CD44 and EpCAM are markers for cancer stem cells; PCNA, cyclin D3, c-Myc, MMP2/9, HES1 and HEY1 are involved in cell proliferation, migration, invasion, tumor growth and metastasis in PC. (b) SMIs block the catalytic site of ASPH, which leads to loss of β-hydroxylase activity and failure of JAG2 binding to Notch1. Thus, Notch signaling is off and its oncogenic effector is inhibited in PC.

Mentions: Figure 10 depicts a working hypothesis of how ASPH contributes to PC development and progression. In this scheme, overexpression of ASPH is followed by translocation to the cell surface where it directly interacts with Notch (Fig. 4). Notch receptors contain 36 EGF-like repeats in the extracellular domain (NECD), which are the substrates of ASPH β-hydroxylase. ASPH may facilitate the interactions of the Notch receptors with their ligands (such as JAG and DLL). It is hypothesized that enhanced Notch receptor-ligand interaction leads to the generation of activated Notch1 ICN followed by upregulation of downstream responsive target genes. The net biological effect is to promote cell proliferation, migration, invasion, tumor growth and metastasis, which leads to PC development and progression; this cellular phenotype is attenuated by a SMI of ASPH β-hydroxylase activity.


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)

Hypothesis of how ASPH may be involved in the pathogenesis of PC progression through Notch activation [6]The structure of ASPH molecule consists of cytoplasmic (green), transmembrane (purple), luminal region (blue) and catalytic domain (red), which contains the catalytic site (M670HPGTH675). (a) In the presence of β-hydroxylase activity of ASPH, binding of the JAG ligand (green) on one cell to the Notch receptor (purple) on another cell results in two proteolytic cleavages of the receptor. The ADAM10 or TACE (TNF-α-converting enzyme; ADAM17) metalloprotease (black) catalyzes the S2 cleavage and generates a substrate for S3 cleavage by the γ-secretase complex (red). This proteolytic processing mediates release of the Notch intracellular domain (NICD), which enters the nucleus and interacts with the DNA-binding CSL (CBF1, Su(H) and LAG-1) protein. The co-activator Mastermind (Mam) and other transcription factors are recruited to the CSL complex, whereas co-repressors (Co-R) are released. Thus, the Notch signaling is on and the downstream target genes are expressed: CD44 and EpCAM are markers for cancer stem cells; PCNA, cyclin D3, c-Myc, MMP2/9, HES1 and HEY1 are involved in cell proliferation, migration, invasion, tumor growth and metastasis in PC. (b) SMIs block the catalytic site of ASPH, which leads to loss of β-hydroxylase activity and failure of JAG2 binding to Notch1. Thus, Notch signaling is off and its oncogenic effector is inhibited in PC.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 10: Hypothesis of how ASPH may be involved in the pathogenesis of PC progression through Notch activation [6]The structure of ASPH molecule consists of cytoplasmic (green), transmembrane (purple), luminal region (blue) and catalytic domain (red), which contains the catalytic site (M670HPGTH675). (a) In the presence of β-hydroxylase activity of ASPH, binding of the JAG ligand (green) on one cell to the Notch receptor (purple) on another cell results in two proteolytic cleavages of the receptor. The ADAM10 or TACE (TNF-α-converting enzyme; ADAM17) metalloprotease (black) catalyzes the S2 cleavage and generates a substrate for S3 cleavage by the γ-secretase complex (red). This proteolytic processing mediates release of the Notch intracellular domain (NICD), which enters the nucleus and interacts with the DNA-binding CSL (CBF1, Su(H) and LAG-1) protein. The co-activator Mastermind (Mam) and other transcription factors are recruited to the CSL complex, whereas co-repressors (Co-R) are released. Thus, the Notch signaling is on and the downstream target genes are expressed: CD44 and EpCAM are markers for cancer stem cells; PCNA, cyclin D3, c-Myc, MMP2/9, HES1 and HEY1 are involved in cell proliferation, migration, invasion, tumor growth and metastasis in PC. (b) SMIs block the catalytic site of ASPH, which leads to loss of β-hydroxylase activity and failure of JAG2 binding to Notch1. Thus, Notch signaling is off and its oncogenic effector is inhibited in PC.
Mentions: Figure 10 depicts a working hypothesis of how ASPH contributes to PC development and progression. In this scheme, overexpression of ASPH is followed by translocation to the cell surface where it directly interacts with Notch (Fig. 4). Notch receptors contain 36 EGF-like repeats in the extracellular domain (NECD), which are the substrates of ASPH β-hydroxylase. ASPH may facilitate the interactions of the Notch receptors with their ligands (such as JAG and DLL). It is hypothesized that enhanced Notch receptor-ligand interaction leads to the generation of activated Notch1 ICN followed by upregulation of downstream responsive target genes. The net biological effect is to promote cell proliferation, migration, invasion, tumor growth and metastasis, which leads to PC development and progression; this cellular phenotype is attenuated by a SMI of ASPH β-hydroxylase activity.

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