Nigro Alessandra, Mauro Loredana, Giordano Francesca, Panza Salvatore, Iannacone Rina, Liuzzi Grazia Maria, Aquila Saveria, De Amicis Francesca, Cellini Francesco, Indiveri Cesare, Panno Maria Luisa
Department of Biology, Ecology and Earth Sciences, University of Calabria, Arcavacata di Rende (CS), Italy.
Department of Pharmacy and Health and Nutrition Sciences, University of Calabria, Arcavacata di Rende (CS), Italy.
Mol Cancer Ther. 2016 May;15(5):1063-73. doi: 10.1158/1535-7163.MCT-15-0830. Epub 2016 Mar 3.
The chaperone HSP70 protein is widely present in many different tumors and its expression correlates with an increased cell survival, low differentiation, and poor therapeutic outcome in human breast cancer. The intracellular protein has prevalently a cytoprotective function, while the extracellular HSP70 mediates immunologic responses. Evolutionarily, HSPs are well conserved from prokaryotes to eukaryotes, and human HSP70 shows a strong similarity to that of plant origin. In the current article, we have tested the potential effect of recombinant HSP70, from Arabidopsis thaliana, on cell survival and metastatic properties of breast cancer cells. Our data show that HSP70 sustains cell viability in MCF-7 and MDA-MB-231 breast tumoral cells and increases Cyclin D1 and Survivin expression. The extracellular HSP70 triggers cell migration and the activation of MMPs particularly in MDA-MB-231 cells. Furthermore, under UV-induced stress condition, the low levels of phospho-AKT were increased by exogenous HSP70, together with the upregulation of Cyclin D1, particularly in the tumoral cell phenotype. On the other hand, UV increased TP53 expression, and the coincubation of HSP70 lowers the TP53 levels similar to the control. These findings correlate with the cytoprotective and antiapoptotic role of HSPs, as reported in different cellular contexts. This is the first study on mammary cells that highlights how the heterologous HSP70 from Arabidopsis thaliana sustains cell survival prevalently in breast cancer cell types, thus maintaining their metastatic potential. Therefore, targeting HSP70 would be of clinical importance since HSP70 blocking selectively targets tumor cells, in which it supports cell growth and survival. Mol Cancer Ther; 15(5); 1063-73. ©2016 AACR.
伴侣蛋白HSP70广泛存在于许多不同的肿瘤中，其表达与人乳腺癌细胞存活率增加、低分化和不良治疗结果相关。细胞内的这种蛋白通常具有细胞保护功能，而细胞外的HSP70介导免疫反应。从进化角度来看，热休克蛋白从原核生物到真核生物都高度保守，人类HSP70与植物来源的HSP70有很强的相似性。在本文中，我们测试了来自拟南芥的重组HSP70对乳腺癌细胞存活和转移特性的潜在影响。我们的数据表明，HSP70维持MCF-7和MDA-MB-231乳腺肿瘤细胞的活力，并增加细胞周期蛋白D1和生存素的表达。细胞外HSP70尤其在MDA-MB-231细胞中触发细胞迁移和基质金属蛋白酶的激活。此外，在紫外线诱导的应激条件下，外源性HSP70可增加磷酸化AKT的低水平表达，同时上调细胞周期蛋白D1，特别是在肿瘤细胞表型中。另一方面，紫外线增加TP53的表达，而HSP70与TP53共同孵育可降低TP53水平，与对照组相似。这些发现与热休克蛋白在不同细胞环境中所报道的细胞保护和抗凋亡作用相关。这是第一项关于乳腺细胞的研究，突出了来自拟南芥的异源HSP70如何在乳腺癌细胞类型中普遍维持细胞存活，从而维持其转移潜能。因此，靶向HSP70具有临床重要性，因为HSP70阻断可选择性地靶向支持细胞生长和存活的肿瘤细胞。《分子癌症治疗》；15(5)；1063 - 1073。©2016美国癌症研究协会。
