Fig. 9
From: Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion
Combined targeting of mutant KRAS and IKKα abolishes IL-1β-induced NF-κΒ activation and malignant pleural effusion development. a, b Bioluminescent detection of NF-κΒ reporter activity in LLC (a; C57BL/6 Lewis lung carcinoma, KrasG12C) and A549 (b; human lung adenocarcinoma, KrasG12S) cells stably expressing pNGL under PBS or 1 nM TNF- or IL-1β-stimulated conditions (4 h), with or without pretreatment with 1 μM deltarasin, IMD-0354, or 17-DMAG alone or in combination (n = 3 independent experiments). Note four-fold induction of NF-κΒ reporter activity by both TNF and IL-1β. Note also inability of any treatment to block TNF-induced NF-κΒ activation and of any standalone treatment except 17-DMAG to inhibit IL-1β-induced NF-κΒ activation. Finally, note complete abrogation of IL-1β-induced NF-κΒ activation in both cell lines by deltarasin/17-DMAG combination. Data are presented as mean ± s.d. P, probability of no difference by one-way ANOVA (PBS group excluded). Double and triple asterisks (** and ***): P < 0.01 and P < 0.001, respectively, for comparison with PBS by Student’s t-tests. Single and double section symbols (§ and §§): P < 0.05 and P < 0.01, respectively, for comparison with TNF or IL-1β by Bonferroni post-tests. c Malignant pleural disease induced by LLC cells in wild-type C57BL/6 mice treated with deltarasin and/or 17-DMAG. Mice received pleural LLC cells, were allowed 5 days for pleural tumor development, and were randomized to daily intraperitoneal treatments with saline (100 μL), deltarasin, 17-DMAG, or both (both at 15 mg/Kg in 100 μL saline; n is given in Supplementary Table 3). Shown are data summaries of effusion volume and pleural fluid cells and Kaplan–Meier survival plot, as well as representative images of effusions (dashed lines), pleural tumors (t), lungs (l), and hearts (h). Data are presented as mean ± s.d. P, probability of no difference by one-way ANOVA or log-rank test. ns, single, double, and triple (*, **, and ***): P > 0.05, P < 0.05, P < 0.01, and P < 0.001, respectively, for the indicated comparisons by Bonferroni post-tests. Scale bars, 1 cm
