Brusatol, a Nrf2 Inhibitor Targets STAT3 Signaling Cascade in Head and Neck Squamous Cell Carcinoma
Brusatol, a Nrf2 Inhibitor Targets STAT3 Signaling Cascade in Head and Neck Squamous Cell Carcinoma
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DOI：
10.3390/biom9100550
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发表时间：
2019-10-01
期刊：
影响因子：
5.5
通讯作者：
Ahn, Kwang Seok
中科院分区：
文献类型：
--
作者：
Lee, Jong Hyun;Rangappa, Shobith;Ahn, Kwang Seok
STAT3是一种潜在的转录因子，在细胞外信号从受体到细胞核的传递中发挥着至关重要的作用。由于其在广泛的基因调节中的作用，它被认为是主要的转录因子，这可能有助于肿瘤发生。在包括头颈鳞状细胞癌 (HNSCC) 在内的多种人类癌症中观察到 STAT3 持续激活及其信号传导失调。在目前的工作中，我们发现 brusatol (BT) 是多种 HNSCC 细胞中 STAT3 信号通路的潜在阻断剂。来自细胞实验的数据表明，BT 诱导细胞毒性并消除 STAT3 和上游激酶（如 JAK1、JAK2 和 Src）的激活。它降低了核 STAT3 的水平及其 DNA 结合能力。 BT 处理增加了 HNSCC 细胞中annexin-V 阳性细胞的数量，促进了 procaspase-3 和 PARP 裂解，并下调了多种蛋白（Bcl-2、Bcl-xl、survivin）的 mRNA 和蛋白表达。综上所述，brusatol 可以作为 HNSCC 中针对 STAT3 信号通路的有前途的抑制剂。
STAT3 is a latent transcription factor that plays a vital role in the transmission of extracellular signal from receptors to the nucleus. It has been regarded as a master transcription factor due to its role in the regulation of a broad spectrum of genes, which can contribute to oncogenesis. Persistent activation of STAT3 and deregulation of its signaling has been observed in various human cancers including head and neck squamous cell carcinoma (HNSCC). In the present work, we identified brusatol (BT) as a potential blocker of STAT3 signaling pathway in diverse HNSCC cells. The data from the cell-based experiments suggested that BT-induced cytotoxicity and abrogated the activation of STAT3 and that of upstream kinases such as JAK1, JAK2, and Src. It reduced the levels of nuclear STAT3 and its DNA binding ability. BT treatment increased annexin-V-positive cells, promoted procaspase-3 and PARP cleavage, and downregulated the mRNA and protein expression of diverse proteins (Bcl-2, Bcl-xl, survivin) in HNSCC cells. Taken together, brusatol can function as a promising inhibitor targeting STAT3 signaling pathway in HNSCC.