Oncotarget

Research Papers:

Antitumor activity of sulfated hyaluronic acid fragments in pre-clinical models of bladder cancer

Andre R. Jordan, Soum D. Lokeshwar, Luis E. Lopez, Martin Hennig, Juan Chipollini, Travis Yates, Marie C. Hupe, Axel S. Merseburger, Aviva Shiedlin, Wolfgang H. Cerwinka, Kebin Liu and Vinata B. Lokeshwar _

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Oncotarget. 2017; 8:24262-24274. https://doi.org/10.18632/oncotarget.10529

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Abstract

Andre R. Jordan1, Soum D. Lokeshwar2, Luis E. Lopez3, Martin Hennig3,4, Juan Chipollini5, Travis Yates1,+, Marie C. Hupe3,4, Axel S. Merseburger4, Aviva Shiedlin6,*, Wolfgang H. Cerwinka5,♠, Kebin Liu3, Vinata B. Lokeshwar3

1Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, Miami, FL, USA

2Honors Program in Medical Education, University of Miami-Miller School of Medicine, Miami, FL, USA

3Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA

4Department of Urology, University of Lübeck, Lübeck, Germany

5Department of Urology, University of Miami-Miller School of Medicine, Miami, FL, USA

6Drug and Biomaterial R&D, Genzyme Corporation, Cambridge, MA, USA

+Present address: University of Pennsylvania- Department of Cancer Biology, Philadelphia, PA, USA

*Present address: PoroGen Corporation, Woburn, MA, USA

♠Present address: Georgia Pediatric Urology, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA

Correspondence to:

Vinata B. Lokeshwar, email: [email protected]

Keywords: bladder cancer, hyaluronic acid, hyaluronidase, sulfated-HA, targeted therapy

Received: February 22, 2016     Accepted: May 16, 2016     Published: July 11, 2016

ABSTRACT

Tumor cell-derived hyaluronidase HYAL-1 degrades hyaluronic acid (HA) into angiogenic fragments (AGF: 10-12 disaccharides). AGF support tumor growth and progression. Urine and tissue HAase/HYAL-1 levels are sensitive markers for high-grade bladder cancer (BCa) and its metastasis. In preclinical models of BCa, we evaluated whether o-sulfated AGF (sHA-F) inhibits HAase activity and has antitumor activity. At IC50 for HAase activity inhibition (5-20 μg/ml [0.4-1.7 μM]), sHA-F significantly inhibited proliferation, motility and invasion of HYAL-1 expressing BCa cells (253J-Lung, HT1376, UMUC-3), P<0.001. sHA-F did not affect the growth of HYAL-1 non-expressing BCa (5637, RT4, T24, TCCSUP) and normal urothelial (Urotsa, SV-HUC1) cells. sHA-F treatment induced apoptosis by death receptor pathway. sHA-F downregulated transcript and/or protein levels of HA receptors (CD44, RHAMM), p-AKT, β-catenin, pβ-Catenin(S552), Snail and Twist but increased levels of pβ-Catenin(T41/S45), pGSK-3α/β(S21/S9) and E-cadherin. sHA-F also inhibited CD44/Phosphoinositide 3-kinase (PI-3K) complex formation and PI-3K activity. AGF addition or myristoylated-AKT overexpression attenuated sHA-F effects. Contrarily, HYAL-1 expression sensitized RT4 cells to sHA-F treatment. In the 253J-L and HT1376 xenograft models, sHA-F treatment significantly inhibited tumor growth (P<0.001), plausibly by inhibiting angiogenesis and HA receptor-PI-3K/AKT signaling. This study delineates that sHA-F targets tumor-associated HA-HAase system and could be potentially useful in BCa treatment.


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