A small-molecule inhibitor of MDMX suppresses cervical cancer cells via the inhibition of E6-E6AP-p53 axis

Jingwen Zhang, Guohua Yu, Yanting Yang, Yingjie Wang, Mengqi Guo, Qikun Yin, Chunhong Yan, Jingwei Tian, Fenghua Fu, Hongbo Wang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number106128
JournalPharmacological Research
Volume177
DOIs
StatePublished - Mar 2022

Keywords

  • Cervical cancer
  • E6AP
  • MDMX
  • P53
  • Small-molecule inhibitor

ASJC Scopus subject areas

  • Pharmacology

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