Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
J Pathol. 2011 Oct;225(2):285-92. doi: 10.1002/path.2918. Epub 2011 Jun 27.
By activating protective pathways, tumour cells are not only capable of survival in stress, but often associated with increased aggressiveness and metastasis. Activating transcription factor 4 (ATF4) is a major coordinator of tumour cell survival in stress and is commonly overexpressed in tumours. Numerous studies suggested that the ATF4 is a potential therapeutic target for cancer. In this report, we describe that a small ribosomal peptide, RPL41, induced rapid ATF4 degradation. By immunofluorescence staining, RPL41 induced ATF4 relocation from nuclei to cytoplasm, where ATF4 co-stained with a proteasome marker; the RPL41-induced ATF4 relocation and degradation were blocked by the proteasome inhibitor MG132. An in vivo phosphorylation study showed that RPL41 induced ATF4 phosphorylation and serine 219 of ATF4 was essential for RPL41-induced ATF4 degradation. Cells with RPL41 knockdown had significantly increased ATF4, suggesting that RPL41 could play a physiological role in regulating the cellular ATF4 level. RPL41 was capable of inducing tumour cell death and cell cycle arrest; at low dose, RPL41 sensitized tumour cells A549 to the DNA damage agent cisplatin. These studies suggest that RPL41, a small peptide that is chemically synthesizable and capable of self-cell penetration, may have potential as an anti-ATF4 agent for cancer therapy.
通过激活保护途径，肿瘤细胞不仅能够在应激中存活，而且往往与侵袭性和转移增加有关。激活转录因子 4（ATF4）是肿瘤细胞应激生存的主要协调因子，通常在肿瘤中过度表达。许多研究表明，ATF4 是癌症治疗的潜在靶点。在本报告中，我们描述了一种小核糖体肽 RPL41 可诱导 ATF4 快速降解。通过免疫荧光染色，RPL41 将 ATF4 从细胞核重定位到细胞质，在细胞质中 ATF4 与蛋白酶体标记物共染色；蛋白酶体抑制剂 MG132 可阻断 RPL41 诱导的 ATF4 重定位和降解。体内磷酸化研究表明，RPL41 诱导 ATF4 磷酸化，ATF4 的丝氨酸 219 对 RPL41 诱导的 ATF4 降解至关重要。敲低 RPL41 的细胞中 ATF4 显著增加，表明 RPL41 可能在调节细胞 ATF4 水平方面发挥生理作用。RPL41 能够诱导肿瘤细胞死亡和细胞周期停滞；低剂量时，RPL41 可增强肿瘤细胞 A549 对 DNA 损伤剂顺铂的敏感性。这些研究表明，RPL41 是一种可化学合成且能够自我穿透细胞的小肽，可能具有作为癌症治疗抗 ATF4 药物的潜力。
