Festuccia Claudio, Angelucci Adriano, Gravina Giovanni, Eleuterio Enrica, Vicentini Carlo, Bologna Mauro
Department of Experimental Medicine, University of L'Aquila, Italy.
Exp Cell Res. 2002 Oct 15;280(1):1-11. doi: 10.1006/excr.2002.5609.
Bombesin-like peptides, including the mammalian homologue gastrin-releasing peptide, are highly expressed and secreted by neuroendocrine cells in prostate carcinoma tissues and are likely to be related to the progression of this neoplastic disease. Previously, we demonstrated that bombesin increased migration and protease expression in androgen-independent cells. In this work we show that bombesin is able to activate pro-MMP-9 through a mechanism involving the beta1 integrin subunit. In fact, MMP-9 processing was evident only when beta1 integrin was engaged with specific adhesive substrates, such as type I collagen, or when cells were seeded on dishes coated with antibodies against beta1 integrin, resulting in activation of the surface ligand. When exogenous pro-MMP-9 was added to PC3 cells, MMP-9 active forms were produced within 30 min by bombesin-treated cultures while control cultures expressed activated forms only after a longer time and at lower levels. MMP-9 activation required cytoskeleton integrity since this effect was abolished by cytochalasin D. Engagement of beta1 integrin caused an increased membrane-linked uPA activity which was required for MMP-9 activation. The cross talk between bombesin- and beta1-integrin-engaged signals seems to be crucial for the modulation of both membrane-linked uPA activity and MMP-9 activation and triggers complex intracellular signaling pathways requiring activation of tyrosine kinase activity, including that of src and PI3K. The beta1 integrin may be considered an important mechanism by which bombesin induces MMP-9 activation. This finding supports the idea that cellular responses to growth factors may be driven by cell-matrix interactions and stresses the role of neuroendocrine factors in prostate carcinoma progression.
蛙皮素样肽，包括哺乳动物同源物胃泌素释放肽，在前列腺癌组织的神经内分泌细胞中高度表达并分泌，可能与这种肿瘤性疾病的进展有关。此前，我们证明蛙皮素可增加雄激素非依赖性细胞的迁移和蛋白酶表达。在这项研究中，我们表明蛙皮素能够通过涉及β1整合素亚基的机制激活前基质金属蛋白酶-9（pro-MMP-9）。事实上，只有当β1整合素与特定的粘附底物（如I型胶原）结合时，或者当细胞接种在包被有抗β1整合素抗体的培养皿上，导致表面配体激活时，MMP-9的加工才明显。当将外源性pro-MMP-9添加到PC3细胞中时，经蛙皮素处理的培养物在30分钟内产生MMP-9活性形式，而对照培养物仅在较长时间后且以较低水平表达激活形式。MMP-9的激活需要细胞骨架的完整性，因为细胞松弛素D可消除这种作用。β1整合素的结合导致膜结合的尿激酶型纤溶酶原激活物（uPA）活性增加，这是MMP-9激活所必需的。蛙皮素和β1整合素相关信号之间的相互作用似乎对于调节膜结合的uPA活性和MMP-9激活至关重要，并触发需要酪氨酸激酶活性激活的复杂细胞内信号通路，包括src和磷脂酰肌醇-3激酶（PI3K）的活性。β1整合素可能被认为是蛙皮素诱导MMP-9激活的重要机制。这一发现支持了细胞对生长因子的反应可能由细胞-基质相互作用驱动的观点，并强调了神经内分泌因子在前列腺癌进展中的作用。
