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, Sung Hoon Kim

Research output: Contribution to journalArticle

29 Scopus citations

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 sulfatebinding 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.

Original languageEnglish (US)
Pages (from-to)4992-5004
Number of pages13
JournalOncotarget
Volume6
Issue number7
DOIs
StatePublished - Jan 1 2015

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Keywords

  • Gemcitabine
  • Heparan sulfate mimetic
  • PG545
  • Pancreatic cancer
  • Wnt/β-catenin

ASJC Scopus subject areas

  • Oncology

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