2. Academic Validation
  3. O-GlcNAcylation regulation of RIPK1-dependent apoptosis dictates sensitivity to sunitinib in renal cell carcinoma

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.
Xiangbo Zeng 1,  Zhiliang Chen 2,  Yuanchao Zhu 1,  Lei Liu 3,  Zhiyong Zhang 1,  Yongyuan Xiao 1,  Qiong Wang 1,  Shiyu Pang 1,  Fengjin Zhao 4,  Bihong Xu 5,  Mengxin Leng 1,  Xiaocen Liu 1,  Chenxi Hu 1,  Siying Zeng 6,  Fei Li 7,  Wenlian Xie 8,  Wanlong Tan 9,  Zaosong Zheng 10
Affiliations

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: feili20700338@126.com.
  • 8 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, China. Electronic address: xiewl@mail.sysu.edu.cn.
  • 9 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: twl@smu.edu.cn.
  • 10 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. Electronic address: zhengzaosong@smu.edu.cn.
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.

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