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首页> 美国卫生研究院文献>other >HSPA6 augments garlic extract-induced inhibition of proliferation migration and invasion of bladder cancer EJ cells; Implication for cell cycle dysregulation signaling pathway alteration and transcription factor-associated MMP-9 regulation
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HSPA6 augments garlic extract-induced inhibition of proliferation migration and invasion of bladder cancer EJ cells; Implication for cell cycle dysregulation signaling pathway alteration and transcription factor-associated MMP-9 regulation

机译：HSPA6增强大蒜提取物对膀胱癌EJ细胞增殖迁移和侵袭的抑制作用；对细胞周期失调信号通路改变和转录因子相关的MMP-9调控的影响

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Although recent studies have demonstrated the anti-tumor effects of garlic extract (GE), the exact molecular mechanism is still unclear. In this study, we investigated the molecular mechanism associated with the inhibitory action of GE against bladder cancer EJ cell responses. Treatment with GE significantly inhibited proliferation of EJ cells dose-dependently through G2/M-phase cell cycle arrest. This G2/M-phase cell cycle arrest by GE was due to the activation of ATM and CHK2, which appears to inhibit phosphorylation of Cdc25C (Ser216) and Cdc2 (Thr14/Tyr15), this in turn was accompanied by down-regulation of cyclin B1 and up-regulation of p21WAF1. Furthermore, GE treatment was also found to induce phosphorylation of MAPK (ERK1/2, p38MAPK, and JNK) and AKT. In addition, GE impeded the migration and invasion of EJ cells via inhibition of MMP-9 expression followed by decreased binding activities of AP-1, Sp-1, and NF-κB motifs. Based on microarray datasets, we selected Heat shock protein A6 (HSPA6) as the most up-regulated gene responsible for the inhibitory effects of GE. Interestingly, overexpression of HSPA6 gene resulted in an augmentation effect with GE inhibiting proliferation, migration, and invasion of EJ cells. The augmentation effect of HSPA6 was verified by enhancing the induction of G2/M-phase-mediated ATM-CHK2-Cdc25C-p21WAF1-Cdc2 cascade, phosphorylation of MAPK and AKT signaling, and suppression of transcription factor-associated MMP-9 regulation in response to GE in EJ cells. Overall, our novel results indicate that HSPA6 reinforces the GE-mediated inhibitory effects of proliferation, migration, and invasion of EJ cells and may provide a new approach for therapeutic treatment of malignancies.
机译：尽管最近的研究证明了大蒜提取物（GE）的抗肿瘤作用，但确切的分子机制仍不清楚。在这项研究中，我们研究了与GE对抗膀胱癌EJ细胞反应的抑制作用相关的分子机制。 GE处理通过G2 / M期细胞周期阻滞显着抑制EJ细胞的增殖。 GE对G2 / M期细胞周期的阻滞是由于ATM和CHK2的激活，这似乎抑制了Cdc25C（Ser216）和Cdc2（Thr14 / Tyr15）的磷酸化，这反过来又伴随着细胞周期蛋白的下调B1和p21WAF1的上调。此外，还发现GE处理可诱导MAPK（ERK1 / 2，p38MAPK和JNK）和AKT磷酸化。此外，GE通过抑制MMP-9表达，进而降低AP-1，Sp-1和NF-κB基序的结合活性，阻止了EJ细胞的迁移和侵袭。基于微阵列数据集，我们选择了热激蛋白A6（HSPA6）作为负责GE抑制作用的最上调基因。有趣的是，HSPA6基因的过表达导致GE具有抑制EJ细胞增殖，迁移和侵袭的增强作用。通过增强对G2 / M期介导的ATM-CHK2-Cdc25C-p21WAF1-Cdc2级联的诱导，MAPK和AKT信号的磷酸化以及抑制转录因子相关MMP-9调控的反应，验证了HSPA6的增强作用。到EJ细胞中的GE。总体而言，我们的新结果表明，HSPA6增强了GE介导的EJ细胞增殖，迁移和侵袭的抑制作用，并可能为恶性肿瘤的治疗提供新途径。

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