Curcumol promotes ferroptosis of colon cancer by targeting the ubiquitination and degradation of GPX4
- J Tradit Complement Med. 2024 Aug 21;15(2):170-181. doi: 10.1016/j.jtcme.2024.08.006.
- 1. College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China.
- 2. Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- 3. School of Acupuncture-Moxibustion and Tuina of Nanjing University of Chinese Medicine · School of Health Preservation and Rehabilitation of Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- 4. Department of Medical Oncology, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, 215600, China.
- 5. The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
- 6. Department of Oncology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Background and aim: Colon Cancer (CC) is one of the common malignant tumors in the digestive tract, the prognosis of CC patients has never been satisfying. A Ferrous-dependent form that regulates cell death, plays a key role in Cancer development. As a core regulator of Ferroptosis, GPX4 has become a potential molecular target for the development of antitumor drugs. Curcumol (Cur), a sesquiterpene natural product, it has significant anti-tumor effect. However, whether Cur mediates Ferroptosis in colon Cancer and its mechanism are still unclear. This study aimed to investigate the underlying mechanisms of Cur anti-tumor.
Experimental procedure: By investigating the Cancer Genome Atlas (TCGA) database and tissue immunofluorescence staining was also used to detect the levels of GPX4 protein in CC and matching paracancerous tissues. The anti-CC and pro-ferroptosis effects of Cur were detected in the vivo and vitro experiment. The interaction between Cur and GPX4 was predicted. In addition, the potential mechanism of Cur anti-CC was further discussed. Co-immunoprecipitation was used to confirm Cur-mediated GPX4 ubiquitination.
Results and conclusion: GPX4 was upregulated in CC tissue and was correlated with poor survival of patients. Cur inhibited the proliferation of CC cells, accompanied by regulating Fe2+ overload, Reactive Oxygen Species (ROS) formation, malondialdehyde (MDA) production and superoxide dismutase (SOD) consumption. Furthermore, GPX4 was predicted and verified as the direct target of Cur by molecular docking and structure-based virtual prediction. Meanwhile, Cur could promote the ubiquitination-mediated degradation of GPX4, induce Ferroptosis in CC cells and regulate the expression of ferroptosis-related protein FTH1 and TfR1. In addition, when GPX4 was overexpressed (GPX4-OE), the inhibitory effect of Cur on the expression of GPX4 and ferroptosis-related protein FTH1 and the promotion of TfR1 expression were abolished. Cur could inhibit CC by increasing the ubiquitination degradation level of GPX4 to induce Ferroptosis in CC cells.