Diacylglycerol kinase eta modulates oncogenic properties of lung cancer cells

作者：Nakano T; Iravani A; Kim M; Hozumi Y; Lohse M; Reichert E; Crotty T M; Stafforini D M; Topham M K^*

来源：Clinical and Translational Oncology, 2014, 16(1): 29-35.

DOI：10.1007/s12094-013-1036-y

• Diacylglycerol kinase
• Epidermal growth factor receptor
• Lipid signaling
• Diacylglycerol
• Lung cancer

Lung cancer is a leading cause of cancer deaths and efforts are underway to identify novel therapies to treat these tumors. Diacylglycerol kinase eta (DGK eta), 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 eta would attenuate oncogenic properties of lung cancer cells.
We determined the expression levels of DGK eta 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 eta in lung cancer cells and tested if DGK eta depletion augmented the effects of afatinib, a new generation EGFR inhibitor.
DGK eta 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 eta 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 eta depletion also reduced growth of one of two lung cancer cell lines that harbored mutant K-Ras.
Our data indicate that DGK eta 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.

• 出版日期2014-1