A small-molecule inhibitor of MDMX suppresses cervical cancer cells via the inhibition of E6-E6AP-p53 axis
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 th...
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| Main Authors: | , , , , , , , , , |
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| Format: | Book |
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Elsevier,
2022-03-01T00:00:00Z.
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| Online Access: | Connect to this object online. |
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| Summary: | 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. |
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| Item Description: | 1096-1186 10.1016/j.phrs.2022.106128 |