Abstract
Epithelial cancer of the ovary exhibits the highest mortality rate of all gynecological malignancies in women today, since the disease is often diagnosed in advanced stages. While the treatment of cancer with specific chemical agents or drugs is the favored treatment regimen, chemotherapy resistance greatly impedes successful ovarian cancer chemotherapy. Thus, chemoresistance becomes one of the most critical clinical issues confronted when treating patients with ovarian cancer. Convincing evidence hints that dysregulation of E3 ubiquitin ligases is a key factor in the development and maintenance of ovarian cancer chemoresistance. This review outlines recent advancement in our understanding of the emerging roles of E3 ubiquitin ligases in ovarian cancer chemoresistance. We also highlight currently available inhibitors targeting E3 ligase activities and discuss their potential for clinical applications in treating chemoresistant ovarian cancer patients.
Highlights
Ubiquitination in cancerUbiquitin is evolutionarily conserved and modifies proteins post-translationally for degradation or nondegradative signaling
Proteolysis-targeting chimera (PROTAC), a useful technology for targeted protein degradation in cancer therapy, has been applied in the degradation of critical oncoproteins involved in malignant neoplastic disease, especially in hematological malignancies[132]
PROTAC binds to the protein of interest to recruit E3 ubiquitin ligase which in turn proximity-induce ubiquitination of the protein of interest and degradation by endogenous 26S proteasomes[132]
Summary
Ubiquitin is evolutionarily conserved and modifies proteins post-translationally for degradation or nondegradative signaling. E3 ubiquitin ligases have been manifested to play key roles in chemoresistance through degradation of various chemoresistance-related substrates in ovarian cancer. There are roughly 30 HECT domain-containing E3 ligases in mammals Among their many functions, HECT domain E3s determine ubiquitination specificity and play prominent roles in the trafficking of many receptors, regulating the immune response and several signaling pathways in cell proliferation[25]. Similar to canonical RING-type E3s, the RING1 domain of the RBR module binds ubiquitin-loaded E2 enzymes (E2-Ubs), whereas an essential active-site Cys in RING2 recruits ubiquitin from an E2-Ub to generate a covalent E3-Ub intermediate, which is otherwise only seen in HECT-type E3s[29]. E3 ubiquitin ligases play crucial roles in the ubiquitin-proteasome pathway, may be critical to cancer progression and chemoresistance. Multiple studies have indicated prominent roles of E3 ubiquitin ligases in ovarian cancer chemoresistance
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