Title |
CX-5461 induces autophagy and inhibits tumor growth via mammalian target of rapamycin-related signaling pathways in osteosarcoma
|
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Published in |
OncoTargets and therapy, September 2016
|
DOI | 10.2147/ott.s104513 |
Pubmed ID | |
Authors |
Leiming Li, Yan Li, Jiansong Zhao, Shuli Fan, Liguo Wang, Xu Li |
Abstract |
Osteosarcoma (OS) is the most common primary bone tumor, but molecular mechanisms of the disease have not been well understood, and treatment of metastatic OS remains a challenge. Rapid ribosomal RNA synthesis in cancer is transcribed by RNA polymerase I, which results in unbridled cell growth. The recent discovery of CX-5461, a selective RNA polymerase I inhibitor, exerted its inhibitory effect of ribosomal RNA synthesis and antiproliferative potency. Here, we demonstrate that CX-5461 induces G2 arrest in the cell cycle and expression of microtubule-associated protein 1 light chain 3 II isoform in OS cell lines. Autophagic vacuoles could be observed in electron microscopy and 3-methyladenine prevented cell death mediated by CX-5461. Moreover, it significantly augmented phosphorylated AMP-Activated Protein Kinases α (p-AMPK α). (Thr(172)) expression in U2-OS cells and decreased p-Akt (Ser(473)) expression in MNNG cells, respectively, which repressed their downstream effector, mammalian target of rapamycin. On the other hand, CX-5461 increased p53 accumulation and messenger RNA level of its target genes, p21, MDM2, and Sestrin1/2 in U2-OS cells. Knockdown of p53 expression markedly impaired cell death as well as the expression of light chain 3-II and p21 induced by CX-5461. It also significantly enhanced doxorubicin-mediated cytotoxic effect in vitro and in vivo together with additive expression of p53, p21, and light chain 3-II in U2-OS cells. Our data indicate that CX-5461 might induce autophagy via mammalian target of rapamycin-associated signaling pathways dependent on p53 status and exert p53-dependent synergistic antitumor effect combined with doxorubicin in OS. These results suggest that CX-5461 might be promising in clinical therapy for OS, especially cases harboring wild-type p53. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 45 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Master | 7 | 16% |
Student > Bachelor | 6 | 13% |
Researcher | 5 | 11% |
Professor > Associate Professor | 3 | 7% |
Other | 3 | 7% |
Unknown | 14 | 31% |
Readers by discipline | Count | As % |
---|---|---|
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Pharmacology, Toxicology and Pharmaceutical Science | 4 | 9% |
Agricultural and Biological Sciences | 3 | 7% |
Nursing and Health Professions | 1 | 2% |
Other | 0 | 0% |
Unknown | 16 | 36% |