A small-molecule inhibitor of MDMX suppresses cervical cancer cells via the inhibition of E6-E6AP-p53 axis
- Pharmacol Res. 2022 Mar:177:106128. doi: 10.1016/j.phrs.2022.106128.
- 1. Key laboratory of Molecular Pharmacology and Drug Evalution (Yantai University), Ministry of Education; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai university, Yantai, China.
- 2. Department of Pathology, Affiliated Yantai Yuhuangding Hospital, Medical College of Qingdao University, Yantai, China.
- 3. Key laboratory of Molecular Pharmacology and Drug Evalution (Yantai University), Ministry of Education; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai university, Yantai, China; Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, China.
- 4. GRU Cancer Center, Georgia Regents University, Augusta, GA, USA.
- 5. Key laboratory of Molecular Pharmacology and Drug Evalution (Yantai University), Ministry of Education; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai university, Yantai, China. Electronic address: [email protected].
- 6. Key laboratory of Molecular Pharmacology and Drug Evalution (Yantai University), Ministry of Education; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai university, Yantai, China. Electronic address: [email protected].
Dysfunction of p53 is observed in many malignant tumors, which is related to Cancer susceptibility. In cervical Cancer, p53 is primarily degradated through the complex of high-risk human papillomaviruses (HPV) oncoprotein E6 and E6-associated protein (E6AP) ubiquitin Ligase. What is less clear is the mechanism and role of murine double minute X (MDMX) in cervical carcinogenesis due to the inactive status of murine double minute 2 (MDM2). In the current study, XI-011 (NSC146109), a small-molecule inhibitor of MDMX, showed robust anti-proliferation activity against several cervical Cancer cell lines. XI-011 promoted Apoptosis of cervical Cancer cells via stabilizing p53 and activating its transcription activity. Moreover, XI-011 inhibited the growth of xenograft tumor in HeLa tumor-bearing mice, as well as enhanced the cytotoxic activity of cisplatin both in vitro and in vivo. Interestingly, MDMX co-localized with E6AP and seems to be a novel binding partner of E6AP to promote p53 ubiquitination. In conclusion, this work revealed a novel mechanism of ubiquitin-dependent p53 degredation via MDMX-E6AP axis in cervical carcinogenesis, and offered the first evidence that MDMX could be a viable drug target for the treatment of cervical Cancer.