The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine
Metrics: PDF 1977 views | HTML 2544 views | ?
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
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
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.