Identifying drug candidates to target cellular events/signaling that evades von Hippel-Lindau tumor suppressor (VHL) gene interaction is critical for the cure of renal cell carcinoma (RCC). Recently, we characterized a triterpene-squalene derived from marine brown alga. Herein, we investigated the potential of squalene in targeting HIF-signaling and other drivers of RCC progression. Squalene inhibited cell proliferation, induced cell dealth and reverted the cells' metastatic state (migration, clonal expansion) independent of their VHL status. Near-identical inhibition of HIF-1α and HIF-2α and the regulation of downstream targets in VHL wild type and mutant cell lines demonstrated squalene efficacy beyond VHL-HIF interaction. In a rat model of chemically induced RCC, squalene displayed chemopreventive capabilities by substantial reversal of lipid peroxidation, mitochondrial redox regulation, maintaining ∆ψ_m, inflammation [Akt, nuclear factor κB (NF-κB)], angiogenesis (VEGFα), metastasis [matrix metalloproteinase 2 (MMP-2)], and survival (Bax/Bcl2, cytochrome-c, Casp3). Squalene restored glutathione, glutathione reductase, glutathione-s-transferase, catalase, and superoxide dismutase and stabilized alkaline phosphatase, alkaline transaminase, and aspartate transaminase. The correlation of thiobarbituric acid reactive substance with VEGF/NF-κB and negative association of GSH with Casp3 show that squalene employs reduction in ROS regulation. Cytokinesis-block micronuclei (CBMN) assay in VHL^wt/mut cells revealed both direct and bystander effects of squalene with increased micronucleus (MN) frequency. Clastogenicity analysis of rat bone marrow cells demonstrated an anti-clastogenic effect of squalene, with increased polychromatic erythrocytes (PCEs), decreased MNPCE,s and MN normochromatic erythrocytes. Squalene could effectively target HIF signaling that orchestrate RCC evolution. The efficacy of squalene is similar in VHL^wt and VHL^mut RCC cells, and hence, squalene could serve as a promising drug candidate for an RCC cure beyond VHL status and VHL-HIF interaction dependency. Summary: Squalene derived from marine brown algae displays strong anti-cancer (RCC) activity, functionally targeting HIF-signaling pathway, and affects various cellular process. The significance of squalene effect for RCC is highlighted by its efficiency beyond VHL status, designating itself a promising drug candidate.

识别靶向细胞事件/信号的候选药物以逃避 von Hippel-Lindau 肿瘤抑制基因 ( VHL ) 基因相互作用，这对于治愈肾细胞癌 (RCC) 至关重要。最近，我们表征了一种源自海洋褐藻的三萜-角鲨烯。在此，我们研究了角鲨烯在靶向HIF信号和其他 RCC 进展驱动因素方面的潜力。角鲨烯抑制细胞增殖、诱导细胞脱附并恢复细胞的转移状态（迁移、克隆扩增），而与它们的VHL状态无关。HIF-1α和HIF-2α的几乎相同的抑制作用以及VHL中下游靶标的调节野生型和突变细胞系表现出超越VHL - HIF相互作用的角鲨烯功效。在化学诱导的 RCC 大鼠模型中，角鲨烯通过显着逆转脂质过氧化、线粒体氧化还原调节、维持 Δψm 显示出化学预防_能力、炎症 [Akt、核因子 κB (NF-κB)]、血管生成 (VEGFα)、转移 [基质金属蛋白酶 2 (MMP-2)] 和存活 (Bax/Bcl2、细胞色素-c、Casp3)。角鲨烯恢复谷胱甘肽、谷胱甘肽还原酶、谷胱甘肽-s-转移酶、过氧化氢酶和超氧化物歧化酶并稳定碱性磷酸酶、碱性转氨酶和天冬氨酸转氨酶。硫代巴比妥酸反应物质与 VEGF/NF-κB 的相关性以及 GSH 与 Casp3 的负相关表明角鲨烯采用了 ROS 调节的减少。VHL ^wt/mut中的细胞分裂阻滞微核 (CBMN) 测定细胞揭示了角鲨烯的直接和旁观者效应，微核（MN）频率增加。大鼠骨髓细胞的致裂性分析表明角鲨烯具有抗致裂作用，具有增加的多染性红细胞 (PCE)、减少的 MNPCE,s 和 MN 正染性红细胞。角鲨烯可以有效地靶向协调 RCC 进化的HIF信号。角鲨烯在VHL ^wt和VHL ^mut RCC 细胞中的功效相似，因此，角鲨烯可以作为超越VHL状态和VHL - HIF相互作用依赖性的 RCC 治愈的有希望的候选药物。概括：源自海洋褐藻的角鲨烯具有很强的抗癌 (RCC) 活性，功能上靶向HIF信号通路，并影响各种细胞过程。角鲨烯效应对 RCC 的重要性通过其超越VHL状态的效率突出显示，将其指定为有前途的候选药物。