Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
J Cell Mol Med. 2020 Jan;24(1):50-60. doi: 10.1111/jcmm.14295. Epub 2019 Sep 30.
Renal cell carcinoma (RCC) is a heterogeneous histological disease and it is one of the most common kidney cancer. The treatment of RCC has been improved for the past few years, but its mortality still remains high. Chelerythrine (CHE) is a natural benzo[c]phenanthridine alkaloid and a widely used broad-range protein kinase C inhibitor which has anti-cancer effect on various types of human cancer cells. However, its effect on RCC has not been fully elucidated. In this study, we evaluated the effect and mechanism of CHE on RCC cells. Our study showed that CHE induced colony formation inhibition and G2/M cell cycle arrest in a dose-dependent manner in RCC cells. In addition, CHE increased cellular ROS level, leading to endoplasmic reticulum (ER) stress, inactivating STAT3 activities and inducing apoptosis in RCC cells which were suppressed by NAC, a special ROS inhibitor. We further found that both knockdown of ATF4 protein and overexpression of STAT3 protein could reduce CHE-induced apoptosis in Caki cells. These results demonstrated that the apoptosis induced by CHE was mediated by ROS-caused ER stress and STAT3 inactivation. Collectively, our studies provided support for CHE as a potential new therapeutic agent for the management of RCC.
肾细胞癌（RCC）是一种异质性组织学疾病，是最常见的肾癌之一。在过去的几年中，RCC 的治疗已经得到了改善，但它的死亡率仍然很高。白屈菜红碱（CHE）是一种天然苯并[c]菲啶生物碱，也是一种广泛使用的广谱蛋白激酶 C 抑制剂，对各种人类癌细胞具有抗癌作用。然而，其对 RCC 的作用尚未完全阐明。在这项研究中，我们评估了 CHE 对 RCC 细胞的作用及其机制。我们的研究表明，CHE 以剂量依赖性方式诱导 RCC 细胞集落形成抑制和 G2/M 细胞周期阻滞。此外，CHE 增加了细胞内 ROS 水平，导致内质网（ER）应激，从而抑制了 STAT3 活性并诱导 RCC 细胞凋亡，而 ROS 特异性抑制剂 NAC 可抑制该凋亡。我们进一步发现，ATF4 蛋白的敲低和 STAT3 蛋白的过表达均可减少 CHE 诱导的 Caki 细胞凋亡。这些结果表明，CHE 诱导的细胞凋亡是由 ROS 引起的 ER 应激和 STAT3 失活介导的。总之，我们的研究为 CHE 作为治疗 RCC 的潜在新治疗剂提供了依据。
