O-GlcNAcylation regulation of RIPK1-dependent apoptosis dictates sensitivity to sunitinib in renal cell carcinoma

Xiangbo Zeng; Zhiliang Chen; Yuanchao Zhu; Lei Liu; Zhiyong Zhang; Yongyuan Xiao; Qiong Wang; Shiyu Pang; Fengjin Zhao; Bihong Xu; Mengxin Leng; Xiaocen Liu; Chenxi Hu; Siying Zeng; Fei Li; Wenlian Xie; Wanlong Tan; Zaosong Zheng

doi:10.1016/j.drup.2024.101150

O-GlcNAcylation regulation of RIPK1-dependent apoptosis dictates sensitivity to sunitinib in renal cell carcinoma

Drug Resist Updat. 2024 Sep 12:77:101150. doi: 10.1016/j.drup.2024.101150. Online ahead of print.

Authors

Xiangbo Zeng¹, Zhiliang Chen², Yuanchao Zhu¹, Lei Liu³, Zhiyong Zhang¹, Yongyuan Xiao¹, Qiong Wang¹, Shiyu Pang¹, Fengjin Zhao⁴, Bihong Xu⁵, Mengxin Leng¹, Xiaocen Liu¹, Chenxi Hu¹, Siying Zeng⁶, Fei Li⁷, Wenlian Xie⁸, Wanlong Tan⁹, Zaosong Zheng¹⁰

Affiliations

¹ Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
² Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China.
³ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China.
⁴ Department of Urology, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510799, China.
⁵ Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
⁶ School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.
⁷ Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
⁸ Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China. Electronic address: [email protected].
⁹ Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].
¹⁰ Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: [email protected].

PMID: 39276723
DOI: 10.1016/j.drup.2024.101150

Abstract

Receptor interacting protein kinase 1 (RIPK1) has emerged as a key regulatory molecule that influences the balance between cell death and cell survival. Under external stress, RIPK1 determines whether a cell undergoes RIPK-dependent apoptosis (RDA) or survives by activating NF-κB signaling. However, the role and mechanisms of RIPK1 on sunitinib sensitivity in renal cell carcinoma (RCC) remain elusive. In this study, we demonstrated that the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of RIPK1 induces sunitinib resistance in RCC by inhibiting RDA. O-GlcNAc transferase (OGT) specifically interacts with RIPK1 through its tetratricopeptide repeats (TPR) domain and facilitates RIPK1 O-GlcNAcylation. The O-GlcNAcylation of RIPK1 at Ser³³¹, Ser⁴⁴⁰ and Ser⁶⁶⁹ regulates RIPK1 ubiquitination and the formation of the RIPK1/FADD/Caspase-8 complex, thereby inhibiting sunitinib-induced RDA in RCC. Site-specific depletion of O-GlcNAcylation on RIPK1 affects the formation of the RIPK1/FADD/Caspase 8 complex, leading to increased sunitinib sensitivity in RCC. Our data highlight the significance of aberrant RIPK1 O-GlcNAcylation in the development of sunitinib resistance and indicate that targeting RIPK1 O-GlcNAcylation could be a promising therapeutic strategy for RCC.

Keywords: O-GlcNAcylation; OGT; RIPK1; Sunitinib; renal cell carcinoma.