Cyclin-dependent kinases of the mediator complex (CDK8 and CDK19) were described as a signaling intermediates in NK cells. Here, we report for the first time the development and use of CDK8/19 inhibitors to suppress phosphorylation of STAT1 S727 in NK cells and to augment the production of the cytolytic molecules perforin and granzyme B (GZMB).

Jan 31, 2025 · Here, we show that short IL-18 generated by caspase-3 cleavage in cancer cells translocates into the nucleus, selectively affects STAT1 activity and thereby mobilizes NK cells to suppress tumor...

Apr 1, 2018 · Because knockdown of CDK8 in a natural killer (NK) cell line enhances cytotoxicity and NK cells provide the first line of immune defense against transformed cells, we asked whether inhibiting CDK8 would improve NK-cell antitumor responses.

We propose new strategies for the development of CDK8/19 inhibitors by: (i) using CDK8/19 inhibitors as mediators of NK cell activity against solid cancers, as opposed to as tumor-directed agents; (ii) combining CDK8/19 inhibitors with ADCC-enhancing antibodies or T cell activating agents such as SMAC mimetics and PD-1/PDL1 axis modulators and ...

Feb 15, 2019 · Overexpression of CDK8 has been observed in various cancers. It mediates aberrant activation of Wnt/β-catenin signaling pathway, which is initially recognized and best studied in colorectal cancer (CRC). CDK8 acts as an oncogene and represents a potential target for developing novel CDK8 inhibitors in cancer therapeutics.

Aug 15, 2013 · We show that mutation of a single phosphorylation site (Stat1-S727A) enhances NK cell cytotoxicity against a range of tumor cells, accompanied by increased expression of perforin and granzyme B. Stat1-S727A mice display significantly delayed disease onset in NK cell-surveilled tumor models including melanoma, leukemia, and metastasizing breast c...

Because knockdown of CDK8 in a natural killer (NK) cell line enhances cytotoxicity and NK cells provide the first line of immune defense against transformed cells, we asked whether inhibiting CDK8 would improve NK-cell antitumor responses.

Aug 15, 2013 · We show that mutation of a single phosphorylation site (Stat1-S727A) enhances NK cell cytotoxicity against a range of tumor cells, accompanied by increased expression of perforin and granzyme B. Stat1-S727A mice display significantly delayed disease onset in NK cell-surveilled tumor models including melanoma, leukemia, and metastasizing breast ...

Oct 23, 2021 · Recent in silico studies have revealed an inverse correlation between recurrence-free survival and the level of cyclin-dependent kinase 8 (CDK8) in breast cancer patients. CDK8 is known to have...

Mar 16, 2021 · CDK8 has been shown to attenuate natural killer (NK) cell cytotoxicity and tumor surveillance . Moreover, CDK8 knockout in NK cells was shown to prolong survival in a mouse model of...