E3 ubiquitin ligase FBXW11-mediated downregulation of S100A11 promotes sensitivity to PARP inhibitor in ovarian cancer.

Ligang CHEN; Mingyi WANG; Yunge GAO; Yanhong LV; Lianghao ZHAI; Jian DONG; Yan CHEN; Xia LI; Xin GUO; Biliang CHEN; Yi RU; Xiaohui LV

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E3 ubiquitin ligase FBXW11-mediated downregulation of S100A11 promotes sensitivity to PARP inhibitor in ovarian cancer.

Author: Ligang CHEN ¹ ; Mingyi WANG ² ; Yunge GAO ¹ ; Yanhong LV ¹ ; Lianghao ZHAI ¹ ; Jian DONG ¹ ; Yan CHEN ² ; Xia LI ³ ; Xin GUO ⁴ ; Biliang CHEN ¹ ; Yi RU ³ ; Xiaohui LV ¹
Author Information

1. Department of Gynecology and Obstetrics, Xijing Hospital, Air Force Medical University, Xi'an, 710032, China.
2. Department of Gynecology and Obstetrics, The General Hospital of Western Theater Command PLA, Chengdu, 610036, China.
3. Department of Biochemistry and Molecular Biology, Air Force Medical University, Xi'an, 710032, China.
4. Department of Endoscopic Surgery, Chinese People's Liberation Army 986th Hospital, Air Force Medical University, Xi'an, 710054, China.
Publication Type:Journal Article
Keywords: FBXW11; Ovarian cancer; PARPi resistance; S100A11
From: Journal of Pharmaceutical Analysis 2025;15(7):101246-101246
CountryChina
Language:English
Abstract: Resistance to poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi) presents a considerable obstacle in the treatment of ovarian cancer. F-box and tryptophan-aspartic (WD) repeat domain containing 11 (FBXW11) modulates the ubiquitination of growth-and invasion-related factors in lung cancer, colorectal cancer, and osteosarcoma. The function of FBXW11 in PARPi therapy is still ambiguous. In this study, RNA sequencing (RNA-seq) showed that FBXW11 expression was raised in ovarian cancer cells that had been treated with PARPi. FBXW11 was abnormally expressed at low levels in high-grade serous ovarian cancer (HGSOC) tissues, and low levels of FBXW11 were associated with shorter overall survival (OS) and progression-free survival (PFS) in HGSOC patients. Overexpressing FBXW11 made ovarian cancer more sensitive to PARPi, while knocking down FBXW11 made it less sensitive. The four-dimensional (4D) label-free quantitative proteomic analysis revealed that FBXW11 targeted S100 calcium binding protein A11 (S100A11) and promoted its degradation through ubiquitination. The increased degradation of S100A11 led to less efficient DNA damage repair, which in turn contributed to increased PARPi-induced DNA damage. The role of FBXW11 in promoting PARPi sensitivity was also confirmed in xenograft mouse models. In summary, our study confirms that FBXW11 promotes the susceptibility of ovarian cancer cells to PARPi via affecting S100A11-mediated DNA damage repair.