title: Antitumor activity of sulfated hyaluronic acid fragments in pre-clinical models of bladder cancer.
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.
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, Miami, FL, USA.
authors.forename: Andre R
authors.initials: AR
authors.lastname: Jordan
authors.affiliation: Honors Program in Medical Education, University of Miami-Miller School of Medicine, Miami, FL, USA.
authors.forename: Soum D
authors.initials: SD
authors.lastname: Lokeshwar
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Lopez
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.|Department of Urology, University of Lübeck, Lübeck, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hennig
authors.affiliation: Department of Urology, University of Miami-Miller School of Medicine, Miami, FL, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Chipollini
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, University of Miami-Miller School of Medicine, Miami, FL, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Yates
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.|Department of Urology, University of Lübeck, Lübeck, Germany.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Hupe
authors.affiliation: Department of Urology, University of Lübeck, Lübeck, Germany.
authors.forename: Axel S
authors.initials: AS
authors.lastname: Merseburger
authors.affiliation: Drug and Biomaterial R&D, Genzyme Corporation, Cambridge, MA, USA.
authors.forename: Aviva
authors.initials: A
authors.lastname: Shiedlin
authors.affiliation: Department of Urology, University of Miami-Miller School of Medicine, Miami, FL, USA.
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Cerwinka
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA.
authors.forename: Vinata B
authors.initials: VB
authors.lastname: Lokeshwar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006820:Hyaluronic Acid; D019869:Phosphatidylinositol 3-Kinases
keywords: bladder cancer; hyaluronic acid; hyaluronidase; sulfated-HA; targeted therapy