Zhao Zichu, Zhang Xia, Wen Lu, Yi Sha, Hu Jingyu, Ruan Jun, Zhao Fei, Cui Guohui, Fang Jun, Chen Yan
Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Eur J Pharmacol. 2016 Oct 15;789:46-59. doi: 10.1016/j.ejphar.2016.06.048. Epub 2016 Jun 29.
Gambogic acid (GA), the active ingredient from gamboges, has been verified as a potent anti-tumor agent in many cancer cells. Nevertheless, its function in lymphoma, especially in B-cell Non-Hodgkin lymphoma (NHL), remains unclear. Amplification and/or overexpression of steroid receptor coactivator-3 (SRC-3) have been detected in multiple tumors and have confirmed its critical roles in carcinogenesis, progression, metastasis and therapy resistance in these cancers. However, no clinical data have revealed the overexpression of SRC-3 and its role in B-cell NHL. In this study, we demonstrated the anti-tumor effects of GA, which included cell growth inhibition, G1/S phase cell cycle arrest and apoptosis in B-cell NHL. We also verified that SRC-3 was overexpressed in B-cell NHL in both cell lines and lymph node samples from patients. The overexpressed SRC-3 was a central drug target of GA, and its down-regulation subsequently modulated down-stream gene expression, ultimately contributing to apoptosis. Silencing SRC-3 decreased the expression of Bcl-2, Bcl-6 and cyclin D3, but not of NF-κB and IκB-α. GA treatment did not inhibit the activation of AKT signaling pathway, but induced the deacetylation of histone H3 at lysine 9 and lysine 27. Down-regulated SRC-3 was observed to interact with more HDAC1 to mediate the deacetylation of H3. As the component of E3 ligase, Cullin3 was up-regulated and mediated the degradation of SRC-3. Our results demonstrate that GA is a potent anti-tumor agent that can be used for therapy against B-cell NHL, especially against those with an abundance of SRC-3.
藤黄酸（GA）是藤黄中的活性成分，已被证实是一种对多种癌细胞有效的抗肿瘤剂。然而，其在淋巴瘤，尤其是B细胞非霍奇金淋巴瘤（NHL）中的作用仍不清楚。在多种肿瘤中已检测到类固醇受体共激活因子3（SRC-3）的扩增和/或过表达，并证实其在这些癌症的致癌、进展、转移和治疗耐药中起关键作用。然而，尚无临床数据显示SRC-3在B细胞NHL中的过表达及其作用。在本研究中，我们证明了GA的抗肿瘤作用，包括抑制B细胞NHL中的细胞生长、使G1/S期细胞周期停滞和诱导凋亡。我们还证实，在细胞系和患者的淋巴结样本中，SRC-3在B细胞NHL中均过表达。过表达的SRC-3是GA的核心药物靶点，其下调随后调节下游基因表达，最终导致凋亡。沉默SRC-3可降低Bcl-2、Bcl-6和细胞周期蛋白D3的表达，但不影响NF-κB和IκB-α的表达。GA处理并未抑制AKT信号通路的激活，但可诱导组蛋白H3赖氨酸9和赖氨酸27的去乙酰化。观察到下调的SRC-3与更多的HDAC1相互作用以介导H3的去乙酰化。作为E3连接酶的组成部分，Cullin3上调并介导SRC-3的降解。我们的结果表明，GA是一种有效的抗肿瘤剂，可用于治疗B细胞NHL，尤其是针对那些SRC-3含量丰富的患者。
