Chemical compounds that suppress hypoxia-induced stress granule formation enhance cancer drug sensitivity of human cervical cancer HeLa cells
Chemical compounds that suppress hypoxia-induced stress granule formation enhance cancer drug sensitivity of human cervical cancer HeLa cells
复制标题
DOI：
10.1093/jb/mvy062
复制
发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Shikshya Timalsina;Kyoko Arimoto-Matsuzaki;Masami Kitamura;Xiaoyin Xu;Wenzhe Qiu;Mari Ishigami‐Yuasa;H. Kagechika;Y. Hata
中科院分区：
文献类型：
--
作者：
Shikshya Timalsina;Kyoko Arimoto-Matsuzaki;Masami Kitamura;Xiaoyin Xu;Wenzhe Qiu;Mari Ishigami‐Yuasa;H. Kagechika;Y. Hata
在真核细胞中，当暴露于某些类型的应激包括缺氧时，eIF 2 α被几种激酶磷酸化，包括蛋白激酶R（PKR）和PKR样内质网激酶（PERK）。随后，蛋白质翻译停止并形成应激颗粒（SG）。癌细胞在缺氧下形成SG。SGs积累凋亡相关分子并发挥抗凋亡作用。因此，低氧诱导的SG形成有助于癌细胞的耐药性。出于这个原因，SG形成的抑制预期在癌症治疗中是有益的。为了证明这一概念，需要抑制SG形成的化学试剂作为实验工具。我们寻找了抑制SG形成的化合物，并鉴定了β-雌二醇、孕酮和甾烷酮（下文描述为EPS）抑制人宫颈癌HeLa细胞中的SG形成。事实证明，EPS阻断PKR而不是PERK，因此无法抑制大多数癌细胞中的SG形成，其中SG通过PERK形成。然而，在这项研究中，我们使用HeLa细胞作为模型，并证明EPS阻断缺氧诱导的SG形成在HeLa细胞，从而减少耐药性，HeLa细胞获得缺氧。我们的研究结果支持抑制SG形成是控制癌症的有用方法。
In eukaryotic cells, when exposed to certain types of stress including hypoxia, eIF2α is phosphorylated by several kinases including protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK). Subsequently, protein translation is stopped and stress granules (SGs) are formed. Cancer cells form SGs under hypoxia. SGs accumulate apoptosis-related molecules and play anti-apoptotic roles. Thus, hypoxia-induced SG formation contributes to drug resistance in cancer cells. For this reason, inhibition of SG formation is expected to be beneficial in cancer therapy. To prove this concept, chemical reagents that inhibit SG formation are required as experimental tools. We searched for chemical compounds that suppress SG formation and identified that β-estradiol, progesterone, and stanolone (hereafter described as EPS) inhibit SG formation in human cervical cancer HeLa cells. As it turned out, EPS block PKR but not PERK, thus fail to suppress SG formation in most cancer cells, where SGs are formed via PERK. Nevertheless, in this study, we used HeLa cells as a model and demonstrated that EPS block hypoxia-induced SG formation in HeLa cells and consequently reduce drug resistance that HeLa cells acquire under hypoxia. Our findings support that inhibition of SG formation is a useful method to control cancers.