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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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Effect of a SMI (MO-I-1100) on PC tumor growth in subcutaneous (s.c.) tumor model of nude mice(a) ASPH transfected MIA PaCa2 cells had high tumorigenicity compared to MIA PaCa2 cells transfected with empty vector. Growth curve on 8 animals in each group indicated enhanced tumor development induced by ASPH overexpression. (b) represents tumor growth curves derived from MIA PaCa2 cells stably transfected with empty vector or a WT-ASPH expression construct as delivered by lentivirus. Note that anti-tumor effects exhibited by MO-I-1100 were observed only in tumors with exogenous ASPH overexpression. Each group had 10 animals. Effect of MO-I-1100 on Notch signaling in vivo has been observed. Tumors taken from the growth curve that were responsive to MO-I-1100 treatment depicted in (b) were analyzed for Notch signaling compared to untreated control. There were 3 tumors taken from the MO-I-1100 treatment group and 3 from the untreated control. (c) demonstrates that the expression of the Notch1 ICN is substantially downregulated by the SMI of APSH β-hydroxylase activity by IHS. (d) represents reduction in the expression of JAG2, as well as Notch activated genes HES1 and PCNA following MO-I-1100 treatment. Similar inhibitory effects of MO-I-1100 on PC tumor growth in vivo were observed in (e) HPAFII and (f) AsPC-1 cells induced s.c. tumors. These human PC cell lines had high endogenous expression of ASPH as shown in Fig. 1a. *p < 0.05; **p < 0.01.
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Figure 9: Effect of a SMI (MO-I-1100) on PC tumor growth in subcutaneous (s.c.) tumor model of nude mice(a) ASPH transfected MIA PaCa2 cells had high tumorigenicity compared to MIA PaCa2 cells transfected with empty vector. Growth curve on 8 animals in each group indicated enhanced tumor development induced by ASPH overexpression. (b) represents tumor growth curves derived from MIA PaCa2 cells stably transfected with empty vector or a WT-ASPH expression construct as delivered by lentivirus. Note that anti-tumor effects exhibited by MO-I-1100 were observed only in tumors with exogenous ASPH overexpression. Each group had 10 animals. Effect of MO-I-1100 on Notch signaling in vivo has been observed. Tumors taken from the growth curve that were responsive to MO-I-1100 treatment depicted in (b) were analyzed for Notch signaling compared to untreated control. There were 3 tumors taken from the MO-I-1100 treatment group and 3 from the untreated control. (c) demonstrates that the expression of the Notch1 ICN is substantially downregulated by the SMI of APSH β-hydroxylase activity by IHS. (d) represents reduction in the expression of JAG2, as well as Notch activated genes HES1 and PCNA following MO-I-1100 treatment. Similar inhibitory effects of MO-I-1100 on PC tumor growth in vivo were observed in (e) HPAFII and (f) AsPC-1 cells induced s.c. tumors. These human PC cell lines had high endogenous expression of ASPH as shown in Fig. 1a. *p < 0.05; **p < 0.01.

Mentions: Studies were performed to determine if ASPH overexpression can promote tumor growth in Balb/c nude mice inoculated subcutaneously (s.c.) with MIA PaCa2 cells. Tumor growth rates are demonstrated in Fig. 9a, where ASPH overexpression accelerated tumor formation compared to tumors induced by stable vector transfected controls.


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 a SMI (MO-I-1100) on PC tumor growth in subcutaneous (s.c.) tumor model of nude mice(a) ASPH transfected MIA PaCa2 cells had high tumorigenicity compared to MIA PaCa2 cells transfected with empty vector. Growth curve on 8 animals in each group indicated enhanced tumor development induced by ASPH overexpression. (b) represents tumor growth curves derived from MIA PaCa2 cells stably transfected with empty vector or a WT-ASPH expression construct as delivered by lentivirus. Note that anti-tumor effects exhibited by MO-I-1100 were observed only in tumors with exogenous ASPH overexpression. Each group had 10 animals. Effect of MO-I-1100 on Notch signaling in vivo has been observed. Tumors taken from the growth curve that were responsive to MO-I-1100 treatment depicted in (b) were analyzed for Notch signaling compared to untreated control. There were 3 tumors taken from the MO-I-1100 treatment group and 3 from the untreated control. (c) demonstrates that the expression of the Notch1 ICN is substantially downregulated by the SMI of APSH β-hydroxylase activity by IHS. (d) represents reduction in the expression of JAG2, as well as Notch activated genes HES1 and PCNA following MO-I-1100 treatment. Similar inhibitory effects of MO-I-1100 on PC tumor growth in vivo were observed in (e) HPAFII and (f) AsPC-1 cells induced s.c. tumors. These human PC cell lines had high endogenous expression of ASPH as shown in Fig. 1a. *p < 0.05; **p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 9: Effect of a SMI (MO-I-1100) on PC tumor growth in subcutaneous (s.c.) tumor model of nude mice(a) ASPH transfected MIA PaCa2 cells had high tumorigenicity compared to MIA PaCa2 cells transfected with empty vector. Growth curve on 8 animals in each group indicated enhanced tumor development induced by ASPH overexpression. (b) represents tumor growth curves derived from MIA PaCa2 cells stably transfected with empty vector or a WT-ASPH expression construct as delivered by lentivirus. Note that anti-tumor effects exhibited by MO-I-1100 were observed only in tumors with exogenous ASPH overexpression. Each group had 10 animals. Effect of MO-I-1100 on Notch signaling in vivo has been observed. Tumors taken from the growth curve that were responsive to MO-I-1100 treatment depicted in (b) were analyzed for Notch signaling compared to untreated control. There were 3 tumors taken from the MO-I-1100 treatment group and 3 from the untreated control. (c) demonstrates that the expression of the Notch1 ICN is substantially downregulated by the SMI of APSH β-hydroxylase activity by IHS. (d) represents reduction in the expression of JAG2, as well as Notch activated genes HES1 and PCNA following MO-I-1100 treatment. Similar inhibitory effects of MO-I-1100 on PC tumor growth in vivo were observed in (e) HPAFII and (f) AsPC-1 cells induced s.c. tumors. These human PC cell lines had high endogenous expression of ASPH as shown in Fig. 1a. *p < 0.05; **p < 0.01.
Mentions: Studies were performed to determine if ASPH overexpression can promote tumor growth in Balb/c nude mice inoculated subcutaneously (s.c.) with MIA PaCa2 cells. Tumor growth rates are demonstrated in Fig. 9a, where ASPH overexpression accelerated tumor formation compared to tumors induced by stable vector transfected controls.

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