Karalis Theodoros T, Chatzopoulos Athanasios, Kondyli Aikaterini, Aletras Alexios J, Karamanos Nikos K, Heldin Paraskevi, Skandalis Spyros S
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110 Patras, Greece.
Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, SE-751 23 Uppsala, Sweden.
Matrix Biol Plus. 2020 Mar 5;6-7:100031. doi: 10.1016/j.mbplus.2020.100031. eCollection 2020 May.
The oncogenic role of hyaluronan in several aspects of tumor biology has been well established. Recent studies by us and others suggest that inhibition of hyaluronan synthesis could represent an emerging therapeutic approach with significant clinical relevance in controlling different breast cancer subtypes, including triple-negative breast cancer. Epidemiological and preclinical studies have revealed the therapeutic potential of aspirin (acetyl salicylate), a classical anti-inflammatory drug, in patients with cancer. However, the underlying molecular mechanisms remain unknown. The present study demonstrates that salicylate, a break down product of aspirin in vivo, alters the organization of hyaluronan matrices by affecting the expression levels of hyaluronan synthesizing (HAS1, 2, 3) and degrading (HYAL-1, -2) enzymes, and that of hyaluronan receptor CD44. In particular, salicylate was found to potently activate AMPK, a kinase known to inhibit HAS2 activity, and caused a dose-dependent decrease of cell associated (intracellular and membrane-bound) as well as secreted hyaluronan, followed by the down-regulation of HAS2 and the induction of HYAL-2 and CD44 in metastatic breast cancer cells. These salicylate-mediated effects were associated with the redistribution of CD44 and actin cytoskeleton that resulted in a less motile cell phenotype. Interestingly, salicylate inhibited metastatic breast cancer cell proliferation and growth by inducing cell growth arrest without signs of apoptosis as evidenced by the substantial decrease of cyclin D1 protein and the absence of cleaved caspase-3, respectively. Collectively, our study offers a possible direction for the development of new matrix-based targeted treatments of metastatic breast cancer subtypes via inhibition of hyaluronan, a pro-angiogenic, pro-inflammatory and tumor promoting glycosaminoglycan.
透明质酸在肿瘤生物学多个方面的致癌作用已得到充分证实。我们和其他研究人员最近的研究表明，抑制透明质酸合成可能代表一种新兴的治疗方法，在控制包括三阴性乳腺癌在内的不同乳腺癌亚型方面具有重要的临床意义。流行病学和临床前研究已经揭示了经典抗炎药物阿司匹林（乙酰水杨酸）对癌症患者的治疗潜力。然而，其潜在的分子机制仍然未知。本研究表明，阿司匹林在体内的分解产物水杨酸盐通过影响透明质酸合成酶（HAS1、2、3）和降解酶（HYAL-1、-2）以及透明质酸受体CD44的表达水平，改变了透明质酸基质的组织结构。特别是，发现水杨酸盐能有效激活AMPK，一种已知可抑制HAS2活性的激酶，并导致细胞相关（细胞内和膜结合）以及分泌的透明质酸呈剂量依赖性减少，随后转移性乳腺癌细胞中HAS2下调，HYAL-2和CD44上调。这些水杨酸盐介导的效应与CD44和肌动蛋白细胞骨架的重新分布有关，导致细胞运动性降低的表型。有趣的是，水杨酸盐通过诱导细胞生长停滞来抑制转移性乳腺癌细胞的增殖和生长，而没有凋亡迹象，分别表现为细胞周期蛋白D1蛋白的大量减少和裂解的caspase-3的缺失。总的来说，我们的研究为通过抑制透明质酸（一种促血管生成、促炎和促进肿瘤生长的糖胺聚糖）开发基于新基质的转移性乳腺癌亚型靶向治疗提供了一个可能的方向。
