Co-administration phenoxodiol with doxorubicin synergistically inhibit the activity of sphingosine kinase-1 (SphK1), a potential oncogene of osteosarcoma, to suppress osteosarcoma cell growth both in vivo and in vitro
| Autor: | Zhang-ping Gu, Chen Yao, Shichang Yan, Yongjiang Yang, Huimin Ding, Sujia Wu, Zu-yu Wang, Dong Li |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Cancer Research Ceramide Intracellular Space Apoptosis Mice SCID Ceramides chemistry.chemical_compound Mice Cell Line Tumor Genetics medicine Animals Humans Doxorubicin ASK1 Protein kinase B Protein Kinase Inhibitors Cell Proliferation Osteosarcoma Sphingosine biology Cell growth Phenoxodiol JNK Mitogen-Activated Protein Kinases Drug Synergism General Medicine Oncogenes Isoflavones Xenograft Model Antitumor Assays Mitochondria Enzyme Activation Phosphotransferases (Alcohol Group Acceptor) Oncology chemistry Sphingosine kinase 1 Papers Cancer research biology.protein Molecular Medicine Proto-Oncogene Proteins c-akt medicine.drug Signal Transduction |
| Zdroj: | Molecular oncology. 6(4) |
| ISSN: | 1878-0261 |
| Popis: | Elucidation of the mechanisms of chemo-resistance and implementation of strategies to overcome it will be pivotal to improve the survival for osteosarcoma (OS) patients. We here suggest that sphingosine kinase-1 (SphK1) might be the key factor contributing to chemo-resistance in OS. Our Western-blots and immunohistochemistry results showed that SphK1 is over-expressed in multiple clinical OS tissues. Over-expression of SphK1 in OS cell line U2OS promoted its growth and endorsed its resistance against doxorubicin, while knocking-down of SphK1 by shRNA inhibited U2OS cell growth and increased its sensitivity to doxorubicin. Co-administration phenoxodiol with doxorubicin synergistically inhibited SphK1 activity to trigger cellular ceramide accumulation, and achieved synergistic anti-OS growth effect, accompanied with a significant increased of apoptosis and cytotoxicity. Increased cellular level of ceramide by the co-administration induced the association between Akt and Protein Phosphatase 1 (PP1) to dephosphorylate Akt, and to introduce a constitutively active Akt (CA-Akt) restored Akt activation and diminished cell growth inhibition. Further, phenoxodiol and doxorubicin synergistically activated apoptosis signal-regulating kinase 1(ASK1)/c-jun-NH2-kinase (JNK) signaling, which also contributed to cell growth inhibition. Significantly, the role of SphK1 in OS cell growth and the synergistic anti-OS effect of phenoxodiol and doxorubicin were also seen in a mice OS xenograft model. In conclusion, our data suggest that SphK1 might be a critical oncogene of OS and co-administration phenoxodiol with doxorubicin synergistically inhibited the activity of SphK1 to suppress osteosarcoma cell growth both in vivo and in vitro. |
| Databáze: | OpenAIRE |
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