Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype

Xiaoqun Dong; Qiushi Lin; Arihiro Aihara; Yu Li; Chiung-Kuei Huang; Waihong Chung; Qi Tang; Xuesong Chen; Rolf Carlson; Christina Nadolny; Gregory Gabriel; Mark Olsen; Jack R. Wands

doi:10.18632/oncotarget.2840

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This article has been corrected. Correction in: Oncotarget. 2019; 10:6644-6646.

Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype

Xiaoqun Dong, Qiushi Lin, Arihiro Aihara, Yu Li, Chiung-Kuei Huang, Waihong Chung, Qi Tang, Xuesong Chen, Rolf Carlson, Christina Nadolny, Gregory Gabriel, Mark Olsen and Jack R. Wands _

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Oncotarget. 2015; 6:1231-1248. https://doi.org/10.18632/oncotarget.2840

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Abstract

Xiaoqun Dong1,2, Qiushi Lin1,2, Arihiro Aihara3, Yu Li1, Chiung-Kuei Huang3, Waihong Chung3, Qi Tang1, Xuesong Chen1, Rolf Carlson3, Christina Nadolny1, Gregory Gabriel4, Mark Olsen5 and Jack R. Wands3

1 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, The University of Rhode Island, Kingston, RI, USA

2 Current address: Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

3 Liver Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA

4 Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, GA, USA

5 Department of Pharmaceutical Sciences, College of Pharmacy–Glendale, Midwestern University, Glendale, Arizona, USA

Correspondence:

Jack R. Wands, email:

Keywords: Aspartate β-Hydroxylase, oncogenesis, small molecule inhibitor (SMI), malignant phenotype, pancreatic cancer

Received: October 24, 2014 Accepted: November 25, 2014 Published: November 26, 2014

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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Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype

Abstract