期刊
CLINICAL CANCER RESEARCH
卷 17, 期 7, 页码 1839-1849出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-0720
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资金
- Natural Science Foundation of China [81071647, 81071762, 81071780, 81030048, 30770836, 30771110, 30870963, 30872930, 30831160517]
- Program for New Century Excellent Talents in Universities [NCET-07-0877]
- Science and Technology Department of Guangdong Province, China [8251008901000006, 2008A030201006]
- Ministry of Education of China [(2008) 890, 200805580047]
- Fundamental Research Funds for the Central Universities [10ykzd03]
- China Central Government [2009ZX10004-213, 2009ZX09103-041]
- Guangdong Recruitment Program of Creative Research Groups
- [985-III]
Purpose: The present study was to examine the effect of sphingosine kinase-1 (SPHK1) on chemother-apeutics-induced apoptosis in non-small cell lung cancer (NSCLC) cells, which is relatively insensitive to chemotherapy, and its clinical significance in NSCLC progression. Experimental Design: The correlation of SPHK1 expression and clinical features of NSCLC was analyzed in 218 paraffin-embedded archived NSCLC specimens by immunohistochemical analysis. The effect of SPHK1 on apoptosis induced by chemotherapeutics was examined both in vitro and in vivo, using Annexin V staining and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assays. Western blotting and luciferase analysis were performed to examine the impact of SPHK1 on the PI3K/Akt /NF-kappa B signaling. Results: The expression of SPHK1 was markedly increased in NSCLC and correlated with tumor progression and poor survival of patients with NSCLC. Upregulation of SPHK1 significantly inhibited doxorubicin-or docetaxel-induced apoptosis, associated with induction of antiapoptotic proteins Bcl-xl, cIAP1, c-IAP2, and TRAF1. In contrast, silencing SPHK1 expression or inhibiting SPHK1 activity with specific inhibitor, SK1-I, significantly enhanced the sensitivity of NSCLC cells to apoptosis induced by chemotherapeutics both in vitro and in vivo. Moreover, we demonstrated that upregulation of SPHK1 activated the PI3K/Akt/NF-kappa B pathway, and that inhibition of the PI3K/Akt/NF-kappa B pathway abrogated the antiapoptotic effect of SPHK1 on NSCLC cells. Conclusions: Our results suggest that SPHK1 is a potential pharmacologic target for the treatment of NSCLC and inhibition of SPHK1 expression or its kinase activity might represent a novel strategy to sensitize NSCLC to chemotherapy. Clin Cancer Res; 17(7); 1839-49. (C) 2011 AACR.
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