ADCK1 is a potential therapeutic target of osteosarcoma.

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.

Pingyangmycin stimulates apoptosis in human hemangioma-derived endothelial cells through activation of the p53 pathway.

Pingyangmycin (also known as Bleomycin A5) is produced by Streptomyces verticillus var. pingyangensis n.sp., and has anti­tumor activities against a variety of tumor cells. The aim of the present study was to determine the molecular mechanism(s) underlying the therapeutic effects of pingyangmycin against infantile hemangiomas. Human hemangioma­derived endothelial cells (HemECs) were treated with pingyangmycin at varying concentrations (100, 200 or 300 µg/ml), and the morphological changes and apoptosis levels were assessed. The gene expression changes were determined by cDNA microarray technology. Transmission electron microscopy examination revealed that the pingyangmycin­treated HemECs exhibited typical apoptotic characteristics, including chromatin condensation and the formation of apoptotic bodies. Annexin­V staining demonstrated that pingyangmycin caused a significant and dose­dependent induction of apoptosis in the HemECs. In the pingyangmycin­treated HemECs, 4,752 genes demonstrated at least 2­fold expression changes at the mRNA level. Quantitative polymerase chain reaction confirmed that pingyangmycin significantly upregulated the expression of p53, p53­induced protein with death domain, Bax, p53 upregulated modulator of apoptosis and p53 inducible gene 3, and downregulated the expression of murine double minute 2. The data demonstrated that the pro­apoptotic activity of pingyangmycin against infantile hemangiomas involves p53 pathway activation.