Statins targeting mevalonate-geranylgeranyl diphosphate pathway inhibit proliferation in NK/T lymphoma by promoting pyroptosis.

Pyroptosis, an inflammation-driven programmed cell death, plays a pivotal role in the carcinogenicity of various tumors. Given the proven antitumor effects of statins, this study investigated whether statins suppress natural killer /T cell lymphoma (NKTCL) via pyroptosis and the underlying mechanism. NKYS and YT cells were treated with different concentrations of statins. The carcinogenicity of cells was validated through cell viability and invasion assays. The level of cell cycle, apoptosis, and the number of pyroptosis cells were evaluated via flow cytometry. Western-blot and immunofluorescence assays were conducted to verify the expressions of pyroptosis and immunity related proteins. The morphological characteristics of cell pyroptosis were observed via transmission electron microscopy. A subcutaneous transplant tumor model was used to verify the inhibitory effect of fluvastatin (FLU) on NKTCL cells in vivo. FLU inhibited the carcinogenicity of NKTCL cells in a concentration-dependent manner, and activated pyroptosis and its related immunity levels, which were represented by swelling of cell morphology, formation of inflammasome, and elevated expressions of gasdermin D, cleaved caspase-1 and interleukin-1β/18. Administration of pyroptosis inhibitors and exogenous mevalonate (MVA) or geranyl pyrophosphate (GGPP) partially weakened the inhibitory effect of FLU on NKTCL cells both in vitro and in vivo. Lastly, FLU and gemcitabine demonstrated satisfactory synergistic effects in tumor suppression and pyroptosis activation. Our data suggest that FLU represses NKTCL growth by promoting pyroptosis via the MVA-GGPP pathway.