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, Vijayalakshmi Shridhar, Sung Hoon Kim

Research output: Contribution to journalArticle

27 Citations (Scopus)

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
StatePublished - 2015

Fingerprint

gemcitabine
Catenins
Heparitin Sulfate
Carcinogenesis
Pancreatic Neoplasms
Neoplasms
Wnt Signaling Pathway
Cyclin D1
Tumor Cell Line
Matrix Metalloproteinases
Heterografts
Vascular Endothelial Growth Factor A
Intercellular Signaling Peptides and Proteins
Apoptosis
Neoplasm Metastasis
Cell Line
Growth

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine. / Jung, Deok Beom; Yun, Miyong; Kim, Eun Ok; Kim, Jaekwang; Kim, Bonglee; Jung, Ji Hoon; Wang, Enfeng; Mukhopadhyay, Debabrata; Hammond, Edward; Dredge, Keith; Shridhar, Vijayalakshmi; Kim, Sung Hoon.

In: Oncotarget, Vol. 6, No. 7, 2015, p. 4992-5004.

Research output: Contribution to journalArticle

Jung, Deok Beom ; Yun, Miyong ; Kim, Eun Ok ; Kim, Jaekwang ; Kim, Bonglee ; Jung, Ji Hoon ; Wang, Enfeng ; Mukhopadhyay, Debabrata ; Hammond, Edward ; Dredge, Keith ; Shridhar, Vijayalakshmi ; Kim, Sung Hoon. / The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine. In: Oncotarget. 2015 ; Vol. 6, No. 7. pp. 4992-5004.
@article{67d63ccdee264626a545e7e545806dca,
title = "The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine",
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.",
keywords = "Gemcitabine, Heparan sulfate mimetic, Pancreatic cancer, PG545, Wnt/β-catenin",
author = "Jung, {Deok Beom} and Miyong Yun and Kim, {Eun Ok} and Jaekwang Kim and Bonglee Kim and Jung, {Ji Hoon} and Enfeng Wang and Debabrata Mukhopadhyay and Edward Hammond and Keith Dredge and Vijayalakshmi Shridhar and Kim, {Sung Hoon}",
year = "2015",
language = "English (US)",
volume = "6",
pages = "4992--5004",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "7",

}

TY - JOUR

T1 - The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine

AU - Jung, Deok Beom

AU - Yun, Miyong

AU - Kim, Eun Ok

AU - Kim, Jaekwang

AU - Kim, Bonglee

AU - Jung, Ji Hoon

AU - Wang, Enfeng

AU - Mukhopadhyay, Debabrata

AU - Hammond, Edward

AU - Dredge, Keith

AU - Shridhar, Vijayalakshmi

AU - Kim, Sung Hoon

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Gemcitabine

KW - Heparan sulfate mimetic

KW - Pancreatic cancer

KW - PG545

KW - Wnt/β-catenin

UR - http://www.scopus.com/inward/record.url?scp=84925002888&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925002888&partnerID=8YFLogxK

M3 - Article

C2 - 25669977

AN - SCOPUS:84925002888

VL - 6

SP - 4992

EP - 5004

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 7

ER -