H12O-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
CIBERONC, 28029 Madrid, Spain.
Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
Heat shock protein 90 (HSP90) is an important chaperone in lung adenocarcinoma, with relevant protein drivers such as EGFR (epidermal growth factor receptor) and EML4-ALK (echinoderm microtubule-associated protein-like protein4 fused to anaplastic lymphoma kinase) depending on it for their correct function, therefore HSP90 inhibitors show promise as potential treatments for lung adenocarcinoma. To study responses to its inhibition, HSP90 was pharmacologically interrupted by geldanamycin and resorcinol derivatives or with combined inhibition of HSP90 plus HSP70 in lung adenocarcinoma cell lines. Two-dimensional electrophoresis was performed to identify proteomic profiles associated with inhibition which will help to understand the biological basis for the responses. HSP90 inhibition resulted in altered protein profiles that differed according the treatment condition studied. Results revealed 254 differentially expressed proteins after treatments, among which, eukaryotic translation initiation factor3 subunit I (eIF3i) and citrate synthase demonstrated their potential role as response biomarkers. The differentially expressed proteins also enabled signalling pathways involved in responses to be identified; these included apoptosis, serine-glycine biosynthesis and tricarboxylic acid cycle. The proteomic profiles identified here contribute to an improved understanding of HSP90 inhibition and open possibilities for the detection of potential response biomarkers which will be essential to maximize treatment efficacy in lung adenocarcinoma.
热休克蛋白 90（HSP90）是肺腺癌中一种重要的伴侣蛋白，相关蛋白驱动因子如表皮生长因子受体（EGFR）和棘皮动物微管相关蛋白样蛋白 4 与间变性淋巴瘤激酶（EML4-ALK）的正确功能依赖于 HSP90，因此 HSP90 抑制剂有望成为肺腺癌的潜在治疗方法。为了研究对其抑制的反应，通过格尔德霉素和间苯二酚衍生物或联合抑制 HSP90 和 HSP70 在肺腺癌细胞系中对 HSP90 进行药理学干预。通过二维电泳来鉴定与抑制相关的蛋白质组谱，这将有助于了解对抑制的生物学基础。HSP90 抑制导致蛋白质图谱发生改变，具体取决于所研究的治疗条件。结果显示，在治疗后有 254 种差异表达的蛋白质，其中真核翻译起始因子 3 亚基 I（eIF3i）和柠檬酸合酶表现出作为反应生物标志物的潜在作用。差异表达的蛋白质还可以鉴定出参与反应的信号通路；这些包括细胞凋亡、丝氨酸-甘氨酸生物合成和三羧酸循环。这里确定的蛋白质组图谱有助于更好地理解 HSP90 抑制，并为检测潜在的反应生物标志物提供了可能性，这对于最大限度地提高肺腺癌的治疗效果至关重要。
