Compressive stress-induced autophagy promotes invasion of HeLa cells by facilitating protein turnover in vitro
Compressive stress-induced autophagy promotes invasion of HeLa cells by facilitating protein turnover in vitro
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DOI：
10.1016/j.yexcr.2019.04.037
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发表时间：
2019-08-15
影响因子：
3.7
通讯作者：
Maiti, Tapas K.
中科院分区：
文献类型：
--
作者：
Das, Joyjyoti;Agarwal, Tarun;Maiti, Tapas K.
转移仍然是癌症死亡的主要原因。在整个转移过程中，癌细胞会经历机械力，这可能是其迁移、稳态和生存特性的关键。然而，压应力对转移过程中癌细胞适应的潜在机制的影响尚未得到充分探索。在这项研究中，我们研究了压力是否会诱导 HeLa 细胞自噬，并对细胞侵袭性产生潜在影响。为此，我们采用了一种简单的策略，通过对琼脂糖支架封装的 HeLa 细胞海藻酸盐珠施加适当的压缩，在体外创建机械压缩的肿瘤微环境。我们的研究结果证实，压缩会上调自噬，从而促进桩蛋白更新和活跃的 MMP-2 分泌，从而增强 HeLa 细胞的迁移。我们进一步表明，压缩诱导的自噬受到 p38 MAPK 磷酸化的影响，这是由完整膜脂筏介导的过程。识别这种机械触发的细胞反应的作用，指导细胞迁移等关键过程，可能会更好地理解转移性癌症的机械生物学方面，并揭示潜在的治疗靶点。
Metastasis remains the primary cause of cancer mortality. Throughout the process of metastasis, cancer cells experience mechanical forces, which may turn out to be the key towards their migratory, homeostatic and survival characteristics. However, the influence of compressive stress on the underlying mechanism of cancer cell adaptation during metastasis has remained grossly unexplored. In this study, we have investigated whether compressive force induces autophagy in HeLa cells with potential implications in cellular invasiveness. To this end, we have adopted a simple strategy to create the mechanically-compressed tumor microenvironment, in vitro, by applying appropriate compression to agarose-scaffolded HeLa cell-encapsulated alginate beads. Our findings confirm that compression upregulates autophagy, which promotes paxillin turnover and active MMP-2 secretion, leading to enhanced migration of HeLa cells. We further show that autophagy induction by compression is affected by the phosphorylation of p38 MAPKs, a process that is mediated by intact membrane lipid rafts. Identifying the role of such mechanically triggered cellular responses, guiding crucial processes like cell migration, may lead to better understanding of the mechanobiological aspects of metastatic cancer and unveil potential therapeutic targets.