Emodin Induced Necroptosis and Inhibited Glycolysis in the Renal Cancer Cells by Enhancing ROS

Abstract

Renal cell carcinoma (RCC) is a tumor with unpredictable presentation and poor clinical outcome. RCC is always resistant to chemotherapy and radiation, and weakly sensitive to immunotherapeutic agents. Therefore, novel agents and approaches are urgently needed for the treatment of RCC. Emodin, an anthraquinone compound extracted from rhubarb and other traditional Chinese herbs, has been implicated in a wide variety of pharmacological effects, such as anti-inflammatory, antiviral, and antitumor activities. However, its role in RCC remains unknown. In this study, we found that emodin effectively killed renal cancer cells without significant toxicity to noncancerous cell HK-2. Flow cytometry assay with Annexin V-FITC and PI demonstrated that emodin induces necroptosis, but not apoptosis, in renal cancer cells. Meanwhile, the phosphorylation levels of RIP1 and MLKL, the key necroptosis-related proteins, were significantly increased. To explore how emodin inhibits kidney tumor growth, we tested reactive oxygen species (ROS) levels and found that the levels of ROS increased upon emodin treatment in a dose-dependent manner. Further studies demonstrated that emodin induces necroptosis through ROS-mediated activation of JNK signaling pathway and also inhibits glycolysis by downregulation of GLUT1 through ROS-mediated inactivation of the PI3K/AKT signaling pathway. Our findings revealed the potential mechanisms by which emodin suppresses renal cancer cell growth and will help develop novel therapeutic approaches for patients with JNK- or PI3K/AKT-dysregulated renal cancer.