School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Translational Research Institute, Brisbane, QLD 4102, Australia.
Biomolecules. 2020 Apr 28;10(5):682. doi: 10.3390/biom10050682.
Extracellular matrix remodeling has emerged as an important factor in many cancers. Proteoglycans, including versican (VCAN), are regulated via cleavage by the proteolytic actions of A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 motif (ADAMTS) family members. Alterations in the balance between Proteoglycans and ADAMTS enzymes have been proposed to contribute to cancer progression. Here, we analyzed the expression of ADAMTS-15 in human prostate cancer, and investigated the effects of enforced expression in prostate cancer cell lines. ADAMTS-15 was found to be expressed in human prostate cancer biopsies with evidence of co-localization with VCAN and its bioactive cleavage fragment versikine. Enforced expression of ADAMTS-15, but not a catalytically-inactive version, decreased cell proliferation and migration of the 'castrate-resistant' PC3 prostate cancer cell line in vitro, with survival increased. Analysis of 'androgen-responsive' LNCaP prostate cancer cells in vivo in NOD/SCID mice revealed that ADAMTS-15 expression caused slower growing tumors, which resulted in increased survival. This was not observed in castrated mice or with cells expressing catalytically-inactive ADAMTS-15. Collectively, this research identifies the enzymatic function of ADAMTS-15 as having a tumor suppressor role in prostate cancer, possibly in concert with androgens, and that VCAN represents a likely key substrate, highlighting potential new options for the clinic.
细胞外基质重塑已成为许多癌症的一个重要因素。蛋白聚糖，包括 versican（VCAN），通过解整合素样金属蛋白酶与凝血酶 1 型基质金属蛋白酶（ADAMTS）家族成员的蛋白水解作用进行调节。蛋白聚糖和 ADAMTS 酶之间平衡的改变被认为有助于癌症的进展。在这里，我们分析了 ADAMTS-15 在人前列腺癌中的表达，并研究了在前列腺癌细胞系中强制表达的效果。ADAMTS-15 被发现在人前列腺癌活检中表达，有证据表明与 VCAN 及其生物活性裂解片段 versikine 共定位。ADAMTS-15 的强制表达，但不是催化失活的版本，降低了体外“去势抵抗”PC3 前列腺癌细胞系的细胞增殖和迁移，同时增加了存活率。在 NOD/SCID 小鼠体内对“雄激素反应”LNCaP 前列腺癌细胞的分析表明，ADAMTS-15 的表达导致肿瘤生长缓慢，从而增加了存活率。在去势小鼠或表达催化失活 ADAMTS-15 的细胞中没有观察到这种情况。总的来说，这项研究确定了 ADAMTS-15 的酶功能在前列腺癌中具有肿瘤抑制作用，可能与雄激素协同作用，而 VCAN 代表了一个可能的关键底物，突出了临床的新选择。
