Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:5669-5669.

The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine

Deok-Beom Jung, Miyong Yun, Eun-Ok Kim, Jaekwang Kim, Bonglee Kim, Ji Hoon Jung, Enfeng Wang, Debabrata Mukhopadhyay, Edward Hammond, Keith Dredge, Viji Shridhar and Sung-Hoon Kim _

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Oncotarget. 2015; 6:4992-5004. https://doi.org/10.18632/oncotarget.3214

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Abstract

Deok-Beom Jung1,*, Miyong Yun1,*, Eun-Ok Kim1,2, Jaekwang Kim1, Bonglee Kim1, Ji Hoon Jung1, Enfeng Wang3, Debabrata Mukhopadhyay3, Edward Hammond4, Keith Dredge4, Viji Shridhar5,** and Sung-Hoon Kim1,**

1 College of Korean Medicine, Kyung Hee University, Seoul, South Korea

2 Korean Medicine Clinical Trial Center, Kyung Hee University, Seoul, South Korea

3 Department of Biochemistry and Molecular Biology, MN, USA

4 Progen Pharmaceuticals Ltd, Brisbane, Queensland, Australia

5 Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA

* These authors contributed equally to this work

**   These authors are senior authors

Correspondence:

Sung-Hoon Kim, email:

Viji Shridhar, email:

Keywords: PG545, Wnt/β-catenin, pancreatic cancer, heparan sulfate mimetic, gemcitabine

Received: October 19, 2014 Accepted: December 30, 2014 Published: December 31, 2014

Abstract

The heparan sulfate mimetic PG545 has been shown to exert anti-angiogenic and anti-metastatic activity in vitro and in vivo cancer models. Although much of this activity has been attributed to inhibition of heparanase and heparan sulfate-binding growth factors, it was hypothesized that PG545 may additionally disrupt Wnt signaling, an important pathway underlying the malignancy of pancreatic cancer. We show that PG545, by directly interacting with Wnt3a and Wnt7a, inhibits Wnt/β-catenin signaling leading to inhibition of proliferation in pancreatic tumor cell lines. Additionally, we demonstrate for the first time that the combination of PG545 with gemcitabine has strong synergistic effects on viability, motility and apoptosis induction in several pancreatic cell lines. In an orthotopic xenograft mouse model, combination of PG545 with gemcitabine efficiently inhibited tumor growth and metastasis compared to single treatment alone. Also, PG545 treatment alone decreased the levels of β-catenin and its downstream targets, cyclin D1, MMP-7 and VEGF which is consistent with our in vitro data. Collectively, our findings suggest that PG545 exerts anti-tumor activity by disrupting Wnt/β-catenin signaling and combination with gemcitabine should be considered as a novel therapeutic strategy for pancreatic cancer treatment.


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