Abstract
Purpose
Lung cancer is a leading cause of cancer deaths and efforts are underway to identify novel therapies to treat these tumors. Diacylglycerol kinase η (DGKη), 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 DGKη would attenuate oncogenic properties of lung cancer cells.
Methods
We determined the expression levels of DGKη 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 DGKη in lung cancer cells and tested if DGKη depletion augmented the effects of afatinib, a new generation EGFR inhibitor.
Results
DGKη 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 DGKη 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. DGKη depletion also reduced growth of one of two lung cancer cell lines that harbored mutant K-Ras.
Conclusions
Our data indicate that DGKη 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.
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Abbreviations
- EGFR:
-
Epidermal growth factor receptor
- DGK:
-
Diacylglycerol kinase
- DMEM:
-
Dulbecco’s modified Eagle’s medium
- rtTA:
-
Reverse tetracycline-controlled transactivator
- CCSP:
-
Clara cell secretory protein
- PCNA:
-
Proliferating cell nuclear antigen
- NSCLC:
-
Non-small cell lung cancer
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Acknowledgments
This work was supported by the Huntsman Cancer Foundation, the R. Harold Burton Foundation, the National Institutes of Health Grants R01-CA95463 (to M.K.T.) and by P30-CA042014.
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The authors declare no conflicts of interest.
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T. Nakano and A. Iravani contributed equally to this manuscript.
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Nakano, T., Iravani, A., Kim, M. et al. Diacylglycerol kinase η modulates oncogenic properties of lung cancer cells. Clin Transl Oncol 16, 29–35 (2014). https://doi.org/10.1007/s12094-013-1036-y
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DOI: https://doi.org/10.1007/s12094-013-1036-y