Targeting hyaluronidase for cancer therapy

Antitumor activity of sulfated hyaluronic acid in prostate cancer cells

Anaid Benitez, Travis J. Yates, Luis E. Lopez, Wolfgang H. Cerwinka, Ashraf Bakkar, Vinata B. Lokeshwar

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

The tumor cell-derived hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) into proangiogenic fragments that support tumor progression. Although HYAL-1 is a critical determinant of tumor progression and a marker for cancer diagnosis and metastasis prediction, it has not been evaluated as a target for cancer therapy. Similarly, sulfated hyaluronic acid (sHA) has not been evaluated for biological activity, although it is an HAase inhibitor. In this study, we show that sHA is a potent inhibitor of prostate cancer. sHA blocked the proliferation, motility, and invasion of LNCaP, LNCaP-AI, DU145, and LAPC-4 prostate cancer cells, and induced caspase-8-dependent apoptosis associated with downregulation of Bcl-2 and phospho-Bad. sHA inhibited Akt signaling including androgen receptor (AR) phosphorylation, AR activity, nuclear factor kB (NFkB) activation, and VEGF expression. These effects were traced to a blockade in complex formation between phosphoinositide 3-kinase (PI3K) and HA receptors and to a transcriptional downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition. Angiogenic HA fragments or overexpression of myristoylated Akt or HA receptors blunted these effects of sHA, implicating a feedback loop between HA receptors and PI3K/Akt signaling in the mechanism of action. In an animal model, sHA strongly inhibited LNCaP-AI prostate tumor growth without causing weight loss or apparent serum-organ toxicity. Inhibition of tumor growth was accompanied by a significant decrease in tumor angiogenesis and an increase in apoptosis index. Taken together, our findings offer mechanistic insights into the tumor-associated HA-HAase system and a preclinical proof-of-concept of the safety and efficacy of sHA to control prostate cancer growth and progression.

Original languageEnglish
Pages (from-to)4085-4095
Number of pages11
JournalCancer Research
Volume71
Issue number12
DOIs
StatePublished - Jun 15 2011
Externally publishedYes

Fingerprint

Hyaluronoglucosaminidase
Hyaluronic Acid
Prostatic Neoplasms
Neoplasms
Therapeutics
1-Phosphatidylinositol 4-Kinase
Androgen Receptors
Down-Regulation
Growth
Apoptosis
Caspase 8
Vascular Endothelial Growth Factor A
Weight Loss
Prostate

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Benitez, A., Yates, T. J., Lopez, L. E., Cerwinka, W. H., Bakkar, A., & Lokeshwar, V. B. (2011). Targeting hyaluronidase for cancer therapy: Antitumor activity of sulfated hyaluronic acid in prostate cancer cells. Cancer Research, 71(12), 4085-4095. https://doi.org/10.1158/0008-5472.CAN-10-4610

Targeting hyaluronidase for cancer therapy : Antitumor activity of sulfated hyaluronic acid in prostate cancer cells. / Benitez, Anaid; Yates, Travis J.; Lopez, Luis E.; Cerwinka, Wolfgang H.; Bakkar, Ashraf; Lokeshwar, Vinata B.

In: Cancer Research, Vol. 71, No. 12, 15.06.2011, p. 4085-4095.

Research output: Contribution to journalArticle

Benitez, A, Yates, TJ, Lopez, LE, Cerwinka, WH, Bakkar, A & Lokeshwar, VB 2011, 'Targeting hyaluronidase for cancer therapy: Antitumor activity of sulfated hyaluronic acid in prostate cancer cells', Cancer Research, vol. 71, no. 12, pp. 4085-4095. https://doi.org/10.1158/0008-5472.CAN-10-4610
Benitez, Anaid ; Yates, Travis J. ; Lopez, Luis E. ; Cerwinka, Wolfgang H. ; Bakkar, Ashraf ; Lokeshwar, Vinata B. / Targeting hyaluronidase for cancer therapy : Antitumor activity of sulfated hyaluronic acid in prostate cancer cells. In: Cancer Research. 2011 ; Vol. 71, No. 12. pp. 4085-4095.
@article{20fe95cfa4b5458e90b97bb32ab732c0,
title = "Targeting hyaluronidase for cancer therapy: Antitumor activity of sulfated hyaluronic acid in prostate cancer cells",
abstract = "The tumor cell-derived hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) into proangiogenic fragments that support tumor progression. Although HYAL-1 is a critical determinant of tumor progression and a marker for cancer diagnosis and metastasis prediction, it has not been evaluated as a target for cancer therapy. Similarly, sulfated hyaluronic acid (sHA) has not been evaluated for biological activity, although it is an HAase inhibitor. In this study, we show that sHA is a potent inhibitor of prostate cancer. sHA blocked the proliferation, motility, and invasion of LNCaP, LNCaP-AI, DU145, and LAPC-4 prostate cancer cells, and induced caspase-8-dependent apoptosis associated with downregulation of Bcl-2 and phospho-Bad. sHA inhibited Akt signaling including androgen receptor (AR) phosphorylation, AR activity, nuclear factor kB (NFkB) activation, and VEGF expression. These effects were traced to a blockade in complex formation between phosphoinositide 3-kinase (PI3K) and HA receptors and to a transcriptional downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition. Angiogenic HA fragments or overexpression of myristoylated Akt or HA receptors blunted these effects of sHA, implicating a feedback loop between HA receptors and PI3K/Akt signaling in the mechanism of action. In an animal model, sHA strongly inhibited LNCaP-AI prostate tumor growth without causing weight loss or apparent serum-organ toxicity. Inhibition of tumor growth was accompanied by a significant decrease in tumor angiogenesis and an increase in apoptosis index. Taken together, our findings offer mechanistic insights into the tumor-associated HA-HAase system and a preclinical proof-of-concept of the safety and efficacy of sHA to control prostate cancer growth and progression.",
author = "Anaid Benitez and Yates, {Travis J.} and Lopez, {Luis E.} and Cerwinka, {Wolfgang H.} and Ashraf Bakkar and Lokeshwar, {Vinata B.}",
year = "2011",
month = "6",
day = "15",
doi = "10.1158/0008-5472.CAN-10-4610",
language = "English",
volume = "71",
pages = "4085--4095",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Targeting hyaluronidase for cancer therapy

T2 - Antitumor activity of sulfated hyaluronic acid in prostate cancer cells

AU - Benitez, Anaid

AU - Yates, Travis J.

AU - Lopez, Luis E.

AU - Cerwinka, Wolfgang H.

AU - Bakkar, Ashraf

AU - Lokeshwar, Vinata B.

PY - 2011/6/15

Y1 - 2011/6/15

N2 - The tumor cell-derived hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) into proangiogenic fragments that support tumor progression. Although HYAL-1 is a critical determinant of tumor progression and a marker for cancer diagnosis and metastasis prediction, it has not been evaluated as a target for cancer therapy. Similarly, sulfated hyaluronic acid (sHA) has not been evaluated for biological activity, although it is an HAase inhibitor. In this study, we show that sHA is a potent inhibitor of prostate cancer. sHA blocked the proliferation, motility, and invasion of LNCaP, LNCaP-AI, DU145, and LAPC-4 prostate cancer cells, and induced caspase-8-dependent apoptosis associated with downregulation of Bcl-2 and phospho-Bad. sHA inhibited Akt signaling including androgen receptor (AR) phosphorylation, AR activity, nuclear factor kB (NFkB) activation, and VEGF expression. These effects were traced to a blockade in complex formation between phosphoinositide 3-kinase (PI3K) and HA receptors and to a transcriptional downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition. Angiogenic HA fragments or overexpression of myristoylated Akt or HA receptors blunted these effects of sHA, implicating a feedback loop between HA receptors and PI3K/Akt signaling in the mechanism of action. In an animal model, sHA strongly inhibited LNCaP-AI prostate tumor growth without causing weight loss or apparent serum-organ toxicity. Inhibition of tumor growth was accompanied by a significant decrease in tumor angiogenesis and an increase in apoptosis index. Taken together, our findings offer mechanistic insights into the tumor-associated HA-HAase system and a preclinical proof-of-concept of the safety and efficacy of sHA to control prostate cancer growth and progression.

AB - The tumor cell-derived hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) into proangiogenic fragments that support tumor progression. Although HYAL-1 is a critical determinant of tumor progression and a marker for cancer diagnosis and metastasis prediction, it has not been evaluated as a target for cancer therapy. Similarly, sulfated hyaluronic acid (sHA) has not been evaluated for biological activity, although it is an HAase inhibitor. In this study, we show that sHA is a potent inhibitor of prostate cancer. sHA blocked the proliferation, motility, and invasion of LNCaP, LNCaP-AI, DU145, and LAPC-4 prostate cancer cells, and induced caspase-8-dependent apoptosis associated with downregulation of Bcl-2 and phospho-Bad. sHA inhibited Akt signaling including androgen receptor (AR) phosphorylation, AR activity, nuclear factor kB (NFkB) activation, and VEGF expression. These effects were traced to a blockade in complex formation between phosphoinositide 3-kinase (PI3K) and HA receptors and to a transcriptional downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition. Angiogenic HA fragments or overexpression of myristoylated Akt or HA receptors blunted these effects of sHA, implicating a feedback loop between HA receptors and PI3K/Akt signaling in the mechanism of action. In an animal model, sHA strongly inhibited LNCaP-AI prostate tumor growth without causing weight loss or apparent serum-organ toxicity. Inhibition of tumor growth was accompanied by a significant decrease in tumor angiogenesis and an increase in apoptosis index. Taken together, our findings offer mechanistic insights into the tumor-associated HA-HAase system and a preclinical proof-of-concept of the safety and efficacy of sHA to control prostate cancer growth and progression.

UR - http://www.scopus.com/inward/record.url?scp=79958816088&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79958816088&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-4610

DO - 10.1158/0008-5472.CAN-10-4610

M3 - Article

VL - 71

SP - 4085

EP - 4095

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 12

ER -