Kong Weiwei, Li Chuang, Qi Qiaofang, Shen Jiahui, Chang Kaiwen
Department of Blood Transfusion, The Third Affiliated Hospital of Xinxiang Medical University, 453000, Xinxiang, China.
Department of Laboratory Medicine, The Third Affiliated Hospital of Xinxiang Medical University, 453000, Xinxiang, China.
Cell Biol Int. 2020 Jan;44(1):177-188. doi: 10.1002/cbin.11217. Epub 2019 Aug 30.
Cardamonin (CD), a naturally occurring chalcone isolated from large black cardamom, was previously reported to suppress the proliferation of breast cancer cells. However, its precise molecular anti-tumor mechanisms have not been well elucidated. In this study, we found that CD markedly inhibited the proliferation of MDA-MB 231 and MCF-7 breast cancer cells through the induction of G2/M arrest and apoptosis. Reactive oxygen species (ROS) plays a pivotal role in the inhibition of CD-induced cell proliferation. Treatment with N-acetyl-cysteine (NAC), an ROS scavenger, blocked CD-induced G2/M arrest and apoptosis in this study. Quenching of ROS by overexpression of catalase also blocked CD-induced cell cycle arrest and apoptosis. We showed that CD enhanced the expression and nuclear translocation of Forkhead box O3 (FOXO3a) via upstream c-Jun N-terminal kinase, inducing the expression of FOXO3a and its target genes, including p21, p27, and Bim. This process led to the reduction of cyclin D1 and enhancement of activated caspase-3 expression. The addition of NAC markedly reversed these effects, knockdown of FOXO3a using small interfering RNA also decreased CD-induced G2/M arrest and apoptosis. In vivo, CD efficiently suppressed the growth of MDA-MB 231 breast cancer xenograft tumors. Taken together, our data provide a molecular mechanistic rationale for CD-induced cell cycle arrest and apoptosis in breast cancer cells.
小豆蔻明（CD）是一种从大砂仁中分离出的天然查尔酮，此前有报道称其可抑制乳腺癌细胞的增殖。然而，其确切的分子抗肿瘤机制尚未完全阐明。在本研究中，我们发现CD通过诱导G2/M期阻滞和凋亡显著抑制MDA-MB 231和MCF-7乳腺癌细胞的增殖。活性氧（ROS）在CD诱导的细胞增殖抑制中起关键作用。在本研究中，用ROS清除剂N-乙酰半胱氨酸（NAC）处理可阻断CD诱导的G2/M期阻滞和凋亡。过氧化氢酶过表达对ROS的淬灭也可阻断CD诱导的细胞周期阻滞和凋亡。我们发现CD通过上游c-Jun氨基末端激酶增强叉头框O3（FOXO3a）的表达和核转位，诱导FOXO3a及其靶基因（包括p21、p27和Bim）的表达。这一过程导致细胞周期蛋白D1减少，活化的半胱天冬酶-3表达增加。添加NAC可显著逆转这些效应，使用小干扰RNA敲低FOXO3a也可降低CD诱导的G2/M期阻滞和凋亡。在体内，CD可有效抑制MDA-MB 231乳腺癌异种移植瘤的生长。综上所述，我们的数据为CD诱导乳腺癌细胞周期阻滞和凋亡提供了分子机制依据。
