Combined inhibition/silencing of diacylglycerol kinase α and ζ simultaneously and synergistically enhances interleukin-2 production in T cells and induces cell death of melanoma cells.
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| Abstract |
The α-isozyme of diacylglycerol kinase (DGK) enhances cancer cell proliferation and, conversely, it promotes the nonresponsive immune state known as T-cell anergy. Moreover, a DGKα-selective inhibitor, CU-3, induced cell death in cancer-derived cells and simultaneously enhanced T-cell interleukin-2 production. In addition to DGKα, DGKζ is also known to induce T-cell anergy. In the present study, we examined whether combined inhibition/silencing of DGKα and DGKζ synergistically enhanced T-cell activity. Combined treatment with CU-3 or DGKα-small interfering RNA (siRNA) and DGKζ-siRNA more potently enhanced T-cell receptor-crosslink-dependent interleukin-2 production in Jurkat T cells than treatment with either alone. Intriguingly, in addition to activating T cells, dual inhibition/silencing of DGKα and DGKζ synergistically reduced viability and increased caspase 3/7 activity in AKI melanoma cells. Taken together, these results indicate that combined inhibition/silencing of DGKα and DGKζ simultaneously and synergistically enhances interleukin-2 production in T cells and induces cell death in melanoma. Therefore, dual inhibition/silencing of these DGK isozymes represents an ideal therapy that potently attenuates cancer cell proliferation and simultaneously enhances immune responses that impact anticancer immunity.
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| Authors | Saki Takao, Rino Akiyama, Fumio Sakane |
| Journal | Journal of cellular biochemistry (J Cell Biochem) Vol. 122 Issue 5 Pg. 494-506 (05 2021) ISSN: 1097-4644 [Electronic] United States |
| PMID | 33399248 (Publication Type: Journal Article) |
| Copyright | © 2020 Wiley Periodicals LLC. |
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