转移是膀胱癌(BC)治疗的主要绊脚石。为了传播,肿瘤细胞必须获得增加的迁移和侵袭能力,这与伪足形成紧密相连。这里,我们揭开了萝卜硫素(SFN)的影响,十字花科蔬菜中的一种异硫氰酸盐,关于伪足和BC转移的组装,及其过程中的分子机制。我们的数据库分析显示,在膀胱肿瘤中,伪足相关基因CTTN,WASL和ACTR2/ARP2上调。SFN通过阻断CTTN-ARP2轴导致BC细胞中的层状足塌陷。SFN通过减少不同侵袭性BC细胞系中的WASL来抑制侵袭足形成和细胞侵袭。ATP的生产,对于伪足的组装至关重要,在膀胱肿瘤中显着增加,并被SFN强烈抑制。过表达AKT1逆转了SFN处理的膀胱癌细胞中ATP的下调,并恢复了丝足和片状足的形态和功能。生物发光成像显示,SFN通过下调Cttn和Arp2表达来抑制裸鼠肺的BC转移。我们的研究揭示了SFN在抑制伪足形成中的作用机制,并强调了转移性膀胱癌治疗的潜在靶向选择。
Metastasis is the primary stumbling block to the treatment of bladder cancer (BC). In order to spread, tumor cells must acquire increased migratory and invasive capacity, which is tightly linked with
pseudopodia formation. Here, we unravel the effects of sulforaphane (SFN), an isothiocyanate in cruciferous vegetables, on the assembly of
pseudopodia and BC metastasis, and its molecular mechanism in the process. Our database analysis revealed that in bladder tumor, the
pseudopodia-associated genes CTTN, WASL and ACTR2/ARP2 are upregulated. SFN caused lamellipodia to collapse in BC cells by blocking the CTTN-ARP2 axis. SFN inhibited invadopodia formation and cell invasion by reducing WASL in different invasive BC cell lines. The production of ATP, essential for the assembly of
pseudopodia, was significantly increased in bladder tumors and strongly inhibited by SFN. Overexpressing AKT1 reversed the downregulation of ATP in SFN-treated bladder cancer cells and restored filopodia and lamellipodia morphology and function. Bioluminescent imaging showed that SFN suppressed BC metastases to the lung of nude mice by downregulating Cttn and Arp2 expression. Our study reveals the mechanism of SFN action in inhibiting
pseudopodia formation, and highlights potential targeting options for the therapy of metastatic bladder cancer.