Dexamethasone and OLT1177 Cooperate in the Reduction of Melanoma Growth by Inhibiting STAT3 Functions

by Selleckchem | Oct 07 2023

The NLRP3 inflammasome is a multimolecular complex that processes inactive IL-1β and IL-18 into proinflammatory cytokines. OLT1177 is an orally active small compound that specifically inhibits NLRP3. Here, B16F10 melanoma were implanted in mice and treated with OLT1177 as well as combined with the glucocorticoid dexamethasone. At sacrifice, OLT1177 treated mice had significantly smaller tumors compared to tumor-bearing mice treated with vehicle. However, the combined treatment of OLT1177 plus dexamethasone revealed a greater suppression of tumor growth. This reduction was accompanied by a downregulation of nuclear and mitochondrial STAT3-dependent gene transcription and by a significant reduction of STAT3 Y705 and S727 phosphorylations in the tumors. In vitro, the human melanoma cell line 1205Lu, stimulated with IL-1α, exhibited significantly lower levels of STAT3 Y705 phosphorylation by the combination treatment, thus affecting the nuclear functions of STAT3. In the same cells, STAT3 serine 727 phosphorylation was also lower, affecting the mitochondrial functions of STAT3. In addition, metabolic analyses revealed a marked reduction of ATP production rate and glycolytic reserve in cells treated with the combination of OLT1177 plus dexamethasone. These findings demonstrate that the combination of OLT1177 and dexamethasone reduces tumor growth by targeting nuclear as well as mitochondrial functions of STAT3.

Comments:

The information you provided describes a study involving the NLRP3 inflammasome, OLT1177 (an inhibitor of NLRP3), and dexamethasone (a glucocorticoid). The study was conducted using B16F10 melanoma implanted in mice and a human melanoma cell line called 1205Lu.

The results of the study showed that treating the mice with OLT1177 resulted in significantly smaller tumors compared to the group treated with a control vehicle. However, when OLT1177 was combined with dexamethasone, there was an even greater suppression of tumor growth. This combination treatment led to a downregulation of nuclear and mitochondrial STAT3-dependent gene transcription.

Furthermore, the combination treatment resulted in a significant reduction in the phosphorylation of STAT3 at the Y705 and S727 sites in the tumors. The phosphorylation of STAT3 at these sites is known to affect its nuclear and mitochondrial functions, respectively. In the human melanoma cell line 1205Lu stimulated with IL-1α, the combination treatment also led to lower levels of STAT3 Y705 phosphorylation, affecting its nuclear functions, as well as lower STAT3 S727 phosphorylation, affecting its mitochondrial functions.

Metabolic analyses conducted in the study revealed a marked reduction in ATP production rate and glycolytic reserve in the cells treated with the combination of OLT1177 and dexamethasone. This suggests that the combination treatment affects the cellular metabolism of the melanoma cells.

Overall, the findings of this study demonstrate that the combination of OLT1177 and dexamethasone can effectively reduce tumor growth by targeting both the nuclear and mitochondrial functions of STAT3.