Diacylglycerol kinase η modulates oncogenic properties of lung cancer cells

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.

The Pleckstrin Homology Domain of Diacylglycerol Kinase η Strongly and Selectively Binds to Phosphatidylinositol 4,5-Bisphosphate

“…The PH of DGK could be an excellent cellular sensor for PI(4,5)P 2 that is equal or superior to the PLC␦1-PH. DGK1 has been reported to be involved in EGFdependent cell proliferation (24) and in the pathogenesis of lung cancer (25) and bipolar disorder (27)(28)(29). It will be interesting to determine what role the DGK isozyme, which has the highly PI(4,5)P 2 -selective binding motif, plays in modulating these physiologically and pathologically important events.…”

“…The data show that DGK is a novel key regulator of the Ras/B-Raf/C-Raf/MEK/ERK signaling pathway. In addi-tion, Nakano et al (25) reported that depleting DGK in lung cancer cell lines harboring a mutant EGF receptor reduced their growth on plastic and in soft agar and augmented the effects of afatinib, an EGF receptor inhibitor. In addition to cancer cells, DGK is also highly expressed in the brain (13,16,26).…”

Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer

“…Notably, a recent report indicates that DGKζ may also play a prominent role in cancer (30). DGKδ has been shown to regulate expression of the epidermal growth factor receptor (EGFR) (31), and DGKη may be a downstream mediator of EGFR signaling in cancer (32). DGKι increases activity of Ras/Rap signaling in cancer (33).…”

Overexpression of Diacylglycerol KinaseηEnhances Gαq-Coupled G Protein–Coupled Receptor Signaling

“…In addition, Moya and colleagues found that DGKh mRNA was expressed at higher levels in postmortem tissue samples from patients with BPD than unaffected controls (Moya et al, 2010). DGKh is a type 2 DGK with two known splice variants (Klauck et al, 1996;Murakami et al, 2003) and was recently implicated in lung cancer (Nakano et al, 2014). However, how alterations in DGKh levels might affect cellular functions or contribute to BPD pathogenesis is currently unknown.…”