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

73 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 (US)
Pages (from-to)4085-4095
Number of pages11
JournalCancer Research
Volume71
Issue number12
DOIs
StatePublished - Jun 15 2011

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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

  • Oncology
  • Cancer Research

Cite this

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, 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.
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