Department of Urology, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
Cancer Res. 2011 Jun 15;71(12):4085-95. doi: 10.1158/0008-5472.CAN-10-4610. Epub 2011 May 9.
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 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 progression.
肿瘤细胞来源的透明质酸酶（HAase）HYAL-1 将透明质酸（HA）降解为支持肿瘤进展的促血管生成片段。尽管 HYAL-1 是肿瘤进展的关键决定因素，也是癌症诊断和转移预测的标志物，但它尚未被评估为癌症治疗的靶点。同样，硫酸化透明质酸（sHA）虽然是 HAase 的抑制剂，但尚未评估其生物学活性。在这项研究中，我们表明 sHA 是一种有效的前列腺癌抑制剂。sHA 阻断了 LNCaP、LNCaP-AI、DU145 和 LAPC-4 前列腺癌细胞的增殖、迁移和侵袭，并诱导与 Bcl-2 和磷酸化 Bad 下调相关的 caspase-8 依赖性细胞凋亡。sHA 抑制 Akt 信号转导，包括雄激素受体（AR）磷酸化、AR 活性、核因子 κB（NFκB）激活和 VEGF 表达。这些作用可追溯到磷酸肌醇 3-激酶（PI3K）与 HA 受体之间复合物形成的阻断以及 HA 受体、CD44 和 RHAMM 的转录下调，同时还抑制了 PI3K。血管生成的 HA 片段或过表达的肉豆蔻酰化 Akt 或 HA 受体削弱了 sHA 的这些作用，表明 HA 受体和 PI3K/Akt 信号转导之间存在反馈回路，这是作用机制的一部分。在动物模型中，sHA 强烈抑制 LNCaP-AI 前列腺肿瘤生长，而不会导致体重减轻或明显的血清-器官毒性。肿瘤生长的抑制伴随着肿瘤血管生成的显著减少和凋亡指数的增加。综上所述，我们的研究结果为肿瘤相关 HA-HAase 系统提供了机制上的见解，并为 sHA 控制前列腺癌生长和进展的安全性和有效性提供了临床前概念验证。
