Diacylglycerol kinase ? modulates oncogenic properties of lung cancer cells

• Autores: T. Nakano, A. Iravani, M. Kim, Y. Hozumi, M. Lohse, E. Reichert, T. M. Crotty, D. M. Stafforini, M. K. Topham
• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 16, Nº. 1, 2014, págs. 29-35
• Idioma: inglés
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• Resumen

  • Purpose Lung cancer is a leading cause of cancer deaths and efforts are underway to identify novel therapies to treat these tumors. Diacylglycerol kinase ? (DGK?), an enzyme that phosphorylates diacylglycerol to form phosphatidic acid, has been shown to modulate MAPK signaling downstream of EGFR, which is an oncogenic driver in some lung cancers. Since mutations in EGFR and K-Ras are common in lung cancer, we hypothesized that limiting the function of DGK? would attenuate oncogenic properties of lung cancer cells.

    Methods We determined the expression levels of DGK? in a mouse models of mutant EGFR and K-Ras lung cancer and in human lung cancer cell lines with activating mutations in either EGFR or K-Ras. We also tested the effects of shRNA-mediated depletion of DGK? in lung cancer cells and tested if DGK? depletion augmented the effects of afatinib, a new generation EGFR inhibitor.

    Results DGK? was expressed in malignant epithelium from mice with mutant EGFR or K-Ras lung cancer. It was also expressed in human lung cancer cell lines with EGFR or K-Ras mutations. Depleting DGK? in lung cancer cell lines, harboring mutant EGFR, reduced their growth on plastic and in soft agar and also augmented the effects of afatinib, an EGFR inhibitor. DGK? depletion also reduced growth of one of two lung cancer cell lines that harbored mutant K-Ras.

    Conclusions Our data indicate that DGK? is a potential therapeutic target in lung cancers, especially those harboring EGFR mutations. Our findings warrant further studies to examine the effects of limiting its function in vivo