期刊
ONCOTARGET
卷 5, 期 20, 页码 9710-9726出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.2344
关键词
Diacylglycerol kinase; Src; 3D tumor growth; chemotherapy resistance; PI3K/Akt
资金
- Spanish Ministry of Education
- Spanish Anti-Cancer Association (AECC)
- Madrid regional government
- Spanish Ministry of Economy and Competitivity [BFU2010-21138]
- Spanish Ministry of Health (Instituto de Salud Carlos III) [RD12/0036/0059]
- Madrid regional government [IMMUNOTHERCAN S2010/BMD-2326]
Diacylglycerol kinase (DGK) a converts diacylglycerol to phosphatidic acid. This lipid kinase sustains survival, migration and invasion of tumor cells, with no effect over untransformed cells, suggesting its potential as a cancer-specific target. Nonetheless the mechanisms that underlie DGKa specific contribution to cancer survival have not been elucidated. Using three-dimensional (3D) colon and breast cancer cell cultures, we demonstrate that DGKa upregulation is part of the transcriptional program that results in Src activation in these culture conditions. Pharmacological or genetic DGKa silencing impaired tumor growth in vivo confirming its function in malignant transformation. DGKa-mediated Src regulation contributed to limit the effect of Src inhibitors, and its transcriptional upregulation in response to PI3K/Akt inhibitors resulted in reduced toxicity. Src oncogenic properties and contribution to pharmacological resistance have been linked to its overactivation in cancer. DGKa participation in this central node helps to explain why its pharmacological inhibition or siRNA-mediated targeting specifically alters tumor viability with no effect on untransformed cells. Our results identify DGKa-mediated stabilization of Src activation as an important mechanism in tumor growth, and suggest that targeting this enzyme, alone or in combination with other inhibitors in wide clinical use, could constitute a treatment strategy for aggressive forms of cancer.
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