Lokeshwar, Vinata BBakkar, AshrafCerwinka, Wolfgang HLopez, Luis E.Cerwinka, Wolfgang H.Lokeshwar, Vinata B.2020-01-112020-01-112011-06https://doi.org/10.1158/0008-5472.CAN-10-4610https://t.ly/WepP9MSA Google ScholarThe 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 κB (NFκB) 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 progressionen-USuniversity of Dspace EgyptEgyptian repositoryMicroenvironmentImmunologyArticlehttps://doi.org/10.1158/0008-5472.CAN-10-4610