HSPA1，HSPA2和其他HSPA蛋白在非小细胞肺癌（NSCLC）中的功能冗余；对NSCLC治疗的意义。,Scientific Reports

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HSPA1，HSPA2和其他HSPA蛋白在非小细胞肺癌（NSCLC）中的功能冗余；对NSCLC治疗的意义。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-10-07 , DOI: 10.1038/s41598-019-50840-7
Damian Robert Sojka ₁ , Agnieszka Gogler-Pigłowska ₁ , Natalia Vydra ₁ , Alexander Jorge Cortez ₁ , Piotr Teodor Filipczak _{1,

2} , Zdzisław Krawczyk ₁ , Dorota Scieglinska ₁

Affiliation

热休克蛋白（HSP）是一大批伴侣，被认为对维持细胞蛋白稳态至关重要。它们在肿瘤中的异常表达可以调节被定义为癌症标志的过程。以前，我们表明，压力诱导型HSPA1和睾丸富集型HSPA2（HSPA（HSP70）家族的高度同源成员）通常在非小细胞肺癌（NSCLC）中过表达。HSPA1是最能表征与癌症相关的伴侣蛋白之一，而HSPA2对癌症的意义仍然知之甚少。先前我们发现在原发性非小细胞肺癌中，HSPA1与预后良好相关，而HSPA2与不良预后相关，表明这些蛋白在癌症中的可能作用不同。因此，在这项工作中，我们研究了HSPA1和HSPA2对NSCLC细胞表型的影响。我们发现，无论是同源选择还是HSPA1和HSPA2基因表达的同时敲低都不会降低NSCLC细胞的生长和化学抗性。尽管最终结果取决于细胞类型，但仅使用泛HSPA抑制剂VER-155008或JG-98阻断HSPA蛋白对NSCLC细胞发挥有效的抗癌作用。Pan-HSPA抑制作用可使NSCLC细胞对硼替佐米敏感，但对铂衍生物不敏感。我们的结果表明，蛋白酶体和HSPA抑制剂似乎是高度侵袭性NSCLC临床前发展的有效药物组合。尽管最终结果取决于细胞类型。Pan-HSPA抑制作用可使NSCLC细胞对硼替佐米敏感，但对铂衍生物不敏感。我们的结果表明，蛋白酶体和HSPA抑制剂似乎是高度侵袭性NSCLC临床前发展的有效药物组合。尽管最终结果取决于细胞类型。Pan-HSPA抑制作用可使NSCLC细胞对硼替佐米敏感，但对铂衍生物不敏感。我们的结果表明，蛋白酶体和HSPA抑制剂似乎是高度侵袭性NSCLC临床前发展的有效药物组合。

"点击查看英文标题和摘要"

Functional redundancy of HSPA1, HSPA2 and other HSPA proteins in non-small cell lung carcinoma (NSCLC); an implication for NSCLC treatment.

Heat shock proteins (HSPs) are a large group of chaperones considered critical for maintaining cellular proteostasis. Their aberrant expression in tumors can modulate the course of processes defined as hallmarks of cancer. Previously, we showed that both stress-inducible HSPA1 and testis-enriched HSPA2, highly homologous members of the HSPA (HSP70) family, are often overexpressed in non-small cell lung carcinoma (NSCLC). HSPA1 is among the best characterized cancer-related chaperones, while the significance of HSPA2 for cancer remains poorly understood. Previously we found that in primary NSCLC, HSPA1 was associated with good prognosis while HSPA2 correlated with bad prognosis, suggesting possible different roles of these proteins in cancer. Therefore, in this work we investigated the impact of HSPA1 and HSPA2 on NSCLC cell phenotype. We found that neither paralog-selective nor simultaneous knockdown of HSPA1 and HSPA2 gene expression reduced growth and chemoresistance of NSCLC cells. Only blocking of HSPA proteins using pan-HSPA inhibitors, VER-155008 or JG-98, exerted potent anticancer effect on NSCLC cells, albeit the final outcome was cell type-dependent. Pan-HSPA inhibition sensitized NSCLC cells to bortezomib, but not to platinum derivates. Our result suggests the inhibitors of proteasome and HSPAs seem an effective drug combination for pre-clinical development in highly aggressive NSCLC.

更新日期：2019-10-07

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