Department of Molecular Biology, College of Natural Sciences, Pusan National University, Pusan 609-735, Korea.
Int J Oncol. 2010 Jul;37(1):97-102. doi: 10.3892/ijo_00000657.
Cancer cells in the inner region of avascularized solid tumours experience metabolical stress by hypoxic and glucose depletion (OGD) and are prone to die by necrosis to form a necrotic core, a common feature of solid tumours. Unlike in apoptosis, where the cellular contents remain packed in the apoptotic bodies that are removed by macrophages, necrosis is characterized by cell membrane rupture, and the release of many cellular proteins including tumour promoting cytokine high mobility group box 1 (HMGB1) into the extra-cellular space. Although ROS produced by metabolic stress are known to cause membrane damage leading to the plasma membrane rupture, its molecular mechanism remains unclear. In this study, we show that some cellular proteins including pro-apoptotic molecules p53, caspase-3, and caspase-9 and a pro-autophagic molecule beclin 1 are not released into the extracellular space but rather aggregated in the cytosol during GD-induced necrosis and that the protein aggregation occurs in a ROS-dependent manner. We also found that Snail, the transcription factor that is induced by GD, was not translocated to the nucleus and aggregated in the cytosol. In addition, Snail interference appeared to block metabolic stress-induced protein aggregation, indicating a critical role(s) of Snail in the protein aggregation. These results demonstrate that in metabolically stressed cancer cells, ROS induce a specific set of cellular proteins to form insoluble aggregates that are highly toxic to cells and trigger the necrosis-associated membrane rupture and HMGB1 release to promote tumour progression.
乏血管实体瘤内部的癌细胞会经历缺氧和葡萄糖耗竭（OGD）引起的代谢应激，容易通过坏死而死亡，从而形成坏死核心，这是实体瘤的一个常见特征。与细胞凋亡不同，细胞内容物在被巨噬细胞清除的凋亡小体中保持包裹，坏死的特征是细胞膜破裂，许多细胞蛋白包括肿瘤促进细胞因子高迁移率族蛋白 1（HMGB1）释放到细胞外空间。虽然代谢应激产生的 ROS 已知会导致膜损伤，从而导致质膜破裂，但它的分子机制尚不清楚。在这项研究中，我们表明，一些细胞蛋白，包括促凋亡分子 p53、caspase-3 和 caspase-9 以及促自噬分子 beclin 1，不会释放到细胞外空间，而是在 GD 诱导的坏死过程中聚集在细胞质中，并且蛋白聚集是 ROS 依赖性的。我们还发现，GD 诱导的转录因子 Snail 没有转位到核内，而是聚集在细胞质中。此外，Snail 干扰似乎阻止了代谢应激诱导的蛋白聚集，表明 Snail 在蛋白聚集中起关键作用。这些结果表明，在代谢应激的癌细胞中，ROS 诱导一组特定的细胞蛋白形成不溶性聚集体，对细胞具有高度毒性，并触发与坏死相关的膜破裂和 HMGB1 释放，以促进肿瘤进展。
