肿瘤抑制因子p53主要作为DNA损伤诱导的细胞凋亡的中介因子，从而有助于基因毒性抗癌治疗的功效。在这里，我们展示了相反的情况，癌细胞可以利用基因毒性应激诱导的p53通过产生全能细胞因子IL-6获得治疗抗性。机制上，可修复或不可修复的DNA损伤激活p53并刺激Caspase-2介导的mouse double minute 2 (MDM2)的裂解，从而形成一个正反馈回路，导致p53蛋白的积累增加。p53在转录水平上控制着主要的三磷酸腺苷(ATP)释放通道pannexin 1 (Panx1)，后者通过依赖于细胞外ATP活化的嘌呤能P2受体及其下游细胞内钙 (iCa2+) / PI3K / Akt / NF-ĸB信号通路，指导IL-6的诱导。因此，p53沉默会损害Panx1和IL-6的表达，并使癌细胞对基因毒性应激敏感。此外，我们证实了IL-6通过减轻DNA损伤、驱动抗凋亡的Bcl-2家族基因表达以及维持癌细胞的迁移和浸润性等方式，削弱了基因毒性抗癌药物的效果。肺癌和全癌队列中对患者生存和相关因素的分析支持了Panx1和IL-6的预后和临床价值。值得注意的是，在基因毒性治疗期间，癌细胞释放的IL-6会促使单核细胞THP-1源性巨噬细胞极化为一种另类（M2型）表型，表现出受损的抗生存活活性，但对癌细胞具有增强的促转移作用，与非极化的巨噬细胞相比。我们的研究揭示了基因毒性诱导的IL-6的精确机制，并暗示针对p53介导的IL-6可能会改善癌细胞对基因毒性抗癌治疗的反应性。 © 2023. 细胞死亡与分化协会（ADMC）。

The tumor suppressor p53 primarily functions as a mediator of DNA damage-induced cell death, thereby contributing to the efficacy of genotoxic anticancer therapeutics. Here, we show, on the contrary, that cancer cells can employ genotoxic stress-induced p53 to acquire treatment resistance through the production of the pleiotropic cytokine interleukin (IL)-6. Mechanistically, DNA damage, either repairable or irreparable, activates p53 and stimulates Caspase-2-mediated cleavage of its negative regulator mouse double minute 2 (MDM2) creating a positive feedback loop that leads to elevated p53 protein accumulation. p53 transcriptionally controls the major adenosine triphosphate (ATP) release channel pannexin 1 (Panx1), which directs IL-6 induction via a mechanism dependent on the extracellular ATP-activated purinergic P2 receptors as well as their downstream intracellular calcium (iCa2+)/PI3K/Akt/NF-ĸB signaling pathway. Thus, p53 silencing impairs Panx1 and IL-6 expression and renders cancer cells sensitive to genotoxic stress. Moreover, we confirm that IL-6 hampers the effectiveness of genotoxic anticancer agents by mitigating DNA damage, driving the expression of anti-apoptotic Bcl-2 family genes, and maintaining the migratory and invasive properties of cancer cells. Analysis of patient survival and relevant factors in lung cancer and pan-cancer cohorts supports the prognostic and clinical values of Panx1 and IL-6. Notably, IL-6 secreted by cancer cells during genotoxic treatments promotes the polarization of monocytic THP-1-derived macrophages into an alternative (M2-like) phenotype that exhibits impaired anti-survival activities but enhanced pro-metastatic effects on cancer cells as compared to nonpolarized macrophages. Our study reveals the precise mechanism for genotoxic-induced IL-6 and suggests that targeting p53-mediated IL-6 may improve the responsiveness of cancer cells to genotoxic anticancer therapy.© 2023. Cell Death Differentiation Association (ADMC).