Institute for Experimental Cancer Research in Pediatrics, Goethe University Frankfurt, 60528 Frankfurt am Main, Germany.
Int J Mol Sci. 2022 Mar 25;23(7):3567. doi: 10.3390/ijms23073567.
Mutations in the Von Hippel-Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.
VHL 基因突变是许多透明细胞肾细胞癌 (ccRCC) 的驱动因素，促进缺氧诱导因子 (HIF)-依赖性肿瘤增殖、转移和血管生成。尽管已经取得了进展，但 ccRCC 通常仍然对传统疗法具有抗性，并且 ccRCC 患者会发生转移和获得性耐药，这凸显了对新型治疗选择的需求。半胱氨酰白三烯受体 1 (CysLTR1) 拮抗剂，如扎鲁司特，在支气管哮喘中用于控制类二十烷酸信号。有趣的是，长期使用扎鲁司特会降低癌症风险，白三烯受体拮抗剂抑制肿瘤生长，但机制仍未被探索。因此，我们旨在了解扎鲁司特介导的 ccRCC 细胞死亡的机制。我们表明，扎鲁司特诱导 VHL 依赖性和 TNFα 非依赖性非凋亡和非坏死性细胞死亡在 ccRCC 细胞中。用抗氧化剂和 PARP-1 抑制剂奥拉帕利可以挽救扎鲁司特诱导的细胞死亡，并且还依赖于 HIF-2α。最后，MG-132 介导的蛋白酶体抑制使 VHL 野生型细胞对扎鲁司特诱导的细胞死亡敏感，并且抑制 HIF-2α 可挽救扎鲁司特和 MG-132 触发的细胞死亡。总之，这些结果强调了 VHL、HIF 和蛋白酶体降解在扎鲁司特诱导的氧化细胞死亡中的重要性，这可能为 ccRCC 提供新的治疗意义。
