ADCK1 is a potential therapeutic target of osteosarcoma.
ADCK1 is a potential therapeutic target of osteosarcoma.
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DOI：
10.1038/s41419-022-05401-8
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发表时间：
2022-11-12
影响因子：
9
通讯作者：
Ling, Zhuo-Yan
中科院分区：
文献类型：
--
作者：
Zhuo, Bao-Biao;Zhu, Lun-Qing;Yao, Chen;Wang, Xi-Hua;Li, Shi-Xian;Wang, Rong;Li, Yuan;Ling, Zhuo-Yan
ADCK1是一种线粒体蛋白，在人骨肉瘤组织和骨肉瘤细胞中表达上调。在原代和已建立的OS细胞中，ADCK1 shRNA或CRISPR/Cas9诱导的ADCK1基因敲除(KO)显著抑制细胞的存活、增殖和迁移，并刺激细胞凋亡激活。反之，异位ADCK1过表达通过促进OS细胞的增殖和迁移而发挥促癌活性。ADCK1耗竭破坏了OS细胞的线粒体功能，导致线粒体膜电位降低、ATP耗竭、活性氧产生。值得注意的是，ADCK1沉默增强了阿霉素诱导的原代OS细胞的凋亡。MTOR激活对OS细胞中ADCK1的表达具有重要意义。MTOR抑制剂雷帕霉素和AZD2014以及mTOR shRNA有效地降低了原代OS细胞ADCK1的表达。在裸鼠皮下移植瘤中，携带ADCK1shRNA或ADCK1KO的移植瘤生长明显受到抑制。此外，ADCK1 KO还能显著抑制Pos-1裸鼠胫骨近端移植瘤的生长。携带ADCK1 shRNA或ADCK1 KO基因的POS-1移植瘤可检测到ADCK1耗竭、细胞凋亡激活和ATP减少。总之，线粒体蛋白ADCK1是OS细胞生长所必需的，是OS的一个新的治疗靶点。
We here showed that ADCK1 (AarF domain-containing kinase 1), a mitochondrial protein, is upregulated in human osteosarcoma (OS) tissues and OS cells. In primary and established OS cells, ADCK1 shRNA or CRISPR/Cas9-induced ADCK1 knockout (KO) remarkably inhibited cell viability, proliferation and migration, and provoked apoptosis activation. Conversely, ectopic ADCK1 overexpression exerted pro-cancerous activity by promoting OS cell proliferation and migration. ADCK1 depletion disrupted mitochondrial functions in OS cells and induced mitochondrial membrane potential reduction, ATP depletion, reactive oxygen species production. Significantly, ADCK1 silencing augmented doxorubicin-induced apoptosis in primary OS cells. mTOR activation is important for ADCK1 expression in OS cells. The mTOR inhibitors, rapamycin and AZD2014, as well as mTOR shRNA, potently decreased ADCK1 expression in primary OS cells. In nude mice, the growth of subcutaneous pOS-1 xenografts was largely inhibited when bearing ADCK1 shRNA or ADCK1 KO construct. Moreover, ADCK1 KO largely inhibited pOS-1 xenograft in situ growth in proximal tibia of nude mice. ADCK1 depletion, apoptosis activation and ATP reduction were detected in pOS-1 xenografts bearing ADCK1 shRNA or ADCK1 KO construct. Together, the mitochondrial protein ADCK1 is required for OS cell growth and is a novel therapeutic target of OS.
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影响因子：
4.6
作者：
Gorska-Ponikowska M;Bastian P;Zauszkiewicz-Pawlak A;Ploska A;Zubrzycki A;Kuban-Jankowska A;Nussberger S;Kalinowski L;Kmiec Z
通讯作者：
Kmiec Z
mTOR：骨肉瘤有吸引力的治疗靶点？
影响因子：
--
作者：
Ding L;Congwei L;Bei Q;Tao Y;Ruiguo W;Heze Y;Bo D;Zhihong L
通讯作者：
Zhihong L
影响因子：
30.8
作者：
Moriarity BS;Otto GM;Rahrmann EP;Rathe SK;Wolf NK;Weg MT;Manlove LA;LaRue RS;Temiz NA;Molyneux SD;Choi K;Holly KJ;Sarver AL;Scott MC;Forster CL;Modiano JF;Khanna C;Hewitt SM;Khokha R;Yang Y;Gorlick R;Dyer MA;Largaespada DA
通讯作者：
Largaespada DA
影响因子：
4.3
作者：
Hsu, Yen-Nien;Shyu, Huey-Wen;Su, Shu-Jem
通讯作者：
Su, Shu-Jem
影响因子：
4.1
作者：
Rickel K;Fang F;Tao J
通讯作者：
Tao J