Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Hawaii, USA.
Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, Yagotoyama, Tempaku, Nagoya, Japan.
Anticancer Drugs. 2021 Jun 1;32(5):558-566. doi: 10.1097/CAD.0000000000001059.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignant diseases and causes a third of cancer-related death. The prognosis and effective treatment of advanced HCC remains poor in spite of the development of novel therapeutic strategies. In the present study, we investigate anticancer effects of the botanical molecule p-hydroxycinnamic acid (HCA) in the HepG2 liver cancer model in vitro. Culturing with HCA (10-1000 nM) suppressed colony formation and growth of HepG2 cells. Mechanistically, culturing with HCA decreased levels of Ras, PI3K, Akt, MAPK, NF-κB p65 and β-catenin, which are linked to processes of cell signaling and transcription, and increased levels of retinoblastoma and regucalcin, which are suppressors for carcinogenesis. These alterations may lead to the suppression of cell growth. Furthermore, culturing with HCA (10-1000 nM) stimulated cell death due to increased caspase-3 levels. Interestingly, the effects of HCA on the growth and death of HepG2 cells were inhibited by culturing with CH223191, an antagonist of aryl hydrocarbon receptor (AHR), suggesting that the flavonoid effects are, at least partly, mediated by activation of AHR signaling. Notably, HCA blocked stimulatory effects of Bay K 8644, an agonist of L-type calcium channel, on the growth of HepG2 cells. Thus, our study demonstrates that HCA suppresses the growth and stimulates the death of human liver cancer HepG2 cells in vitro. The botanical molecule HCA may therefore be a useful tool in the treatment of HCC, providing a novel strategy for the therapy of human liver cancers.
肝细胞癌 (HCC) 是最常见的恶性疾病之一，也是导致三分之一癌症相关死亡的原因。尽管新的治疗策略不断发展，但晚期 HCC 的预后和有效治疗仍然很差。在本研究中，我们研究了植物分子对羟基肉桂酸 (HCA) 在体外 HepG2 肝癌模型中的抗癌作用。用 HCA（10-1000 nM）培养会抑制 HepG2 细胞的集落形成和生长。从机制上讲，用 HCA 培养会降低 Ras、PI3K、Akt、MAPK、NF-κB p65 和 β-catenin 的水平，这些蛋白与细胞信号转导和转录过程有关，并增加视网膜母细胞瘤和 regucalcin 的水平，这两种蛋白是致癌作用的抑制剂。这些变化可能导致细胞生长受到抑制。此外，用 HCA（10-1000 nM）培养会因 caspase-3 水平升高而刺激细胞死亡。有趣的是，用芳基烃受体 (AHR) 拮抗剂 CH223191 培养会抑制 HCA 对 HepG2 细胞生长和死亡的作用，这表明黄酮类化合物的作用至少部分是通过激活 AHR 信号转导来介导的。值得注意的是，HCA 阻断了 L 型钙通道激动剂 Bay K 8644 对 HepG2 细胞生长的刺激作用。因此，我们的研究表明，HCA 抑制人肝癌 HepG2 细胞的体外生长并刺激其死亡。植物分子 HCA 因此可能是治疗 HCC 的有用工具，为人类肝癌的治疗提供了新策略。
