Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells.
Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells.
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DOI：
10.1158/0008-5472.can-10-4610
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发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Lokeshwar VB
中科院分区：
文献类型：
--
作者：
Benitez A;Yates TJ;Lopez LE;Cerwinka WH;Bakkar A;Lokeshwar VB
肿瘤细胞来源的透明质酸酶HYAL-1将透明质酸（HA）降解成支持肿瘤进展的促血管生成片段。虽然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，但尚未将其作为癌症治疗的靶点进行评估。类似地，硫酸化透明质酸（sHA）虽然是HA酶抑制剂，但尚未评价其生物活性。在这项研究中，我们表明sHA是前列腺癌的有效抑制剂。sHA阻断LNCaP、LNCaP-AI、DU 145和LAPC-4前列腺癌细胞的增殖、运动和侵袭，还诱导与Bcl-2和磷酸化Bad下调相关的caspase 8依赖性凋亡。sHA抑制Akt信号传导，包括雄激素受体（AR）磷酸化、AR活性、NF kb活化和VEGF表达。这些作用可追溯到阻断PI 3 K和HA受体之间的复合物形成，以及沿着PI 3 K抑制作用的HA受体、CD 44和RHAMM的转录下调。血管生成HA片段或肉豆蔻酰化Akt或HA受体的过表达减弱了sHA的这些作用，暗示HA受体和PI 3 K/Akt信号传导之间的反馈回路在作用机制中。在动物模型中，sHA强烈抑制LNCaP-AI前列腺肿瘤生长，而不引起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。总之，我们的研究结果提供了对肿瘤相关HA-HAase系统的机制见解，以及sHA控制前列腺癌生长和进展的安全性和有效性的临床前概念验证。
The tumor cell-derived hyaluronidase HYAL-1 degrades hyaluronic acid (HA) into pro-angiogenic 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 a 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, also inducing caspase 8-dependent apoptosis associated with downregulation of Bcl-2 and phospho-Bad. sHA inhibited Akt signaling including androgen receptor (AR) phosphorylation, AR-activity, NFkb activation and VEGF expression. These effects were traced to a blockade in complex formation between 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.