AIM2 promotes renal cell carcinoma progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis

Qi Wang; Su Gao; Yi Shou; Yujie Jia; Zhihao Wei; Yuenan Liu; Jian Shi; Daojia Miao; Qi Miao; Chuanyi Zhao; Chenchen Liu; Hongmei Yang; Tianbo Xu; Xiaoping Zhang

doi:10.7150/ijbs.79853

AIM2 promotes renal cell carcinoma progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis

Int J Biol Sci. 2023 Feb 13;19(4):1266-1283. doi: 10.7150/ijbs.79853. eCollection 2023.

Authors

Qi Wang^{1

2}, Su Gao^{3

4}, Yi Shou^{1

2}, Yujie Jia⁵, Zhihao Wei^{1

2}, Yuenan Liu^{1

2}, Jian Shi^{1

2}, Daojia Miao^{1

2}, Qi Miao^{1

2}, Chuanyi Zhao^{1

2}, Chenchen Liu^{1

2}, Hongmei Yang⁶, Tianbo Xu^{1

2}, Xiaoping Zhang^{1

2

7}

Affiliations

¹ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Institute of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Institute of Gerontology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
⁷ Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China.

Abstract

Renal cell carcinoma (RCC) is a serious threat to people's health due to its rapid progression, and patients easily develop resistance to targeted therapy. The absent in melanoma 2 (AIM2) is a receptor protein that has recently been proposed to play an important role in various diseases. In this study, AIM2 was identified as a new biomarker of RCC and promoted RCC progression and sunitinib resistance in an inflammasome-independent manner. Mechanistically, AIM2 promoted FOXO3a phosphorylation and proteasome degradation, thereby reducing its transcriptional effect on ACSL4 and inhibiting ferroptosis. In summary, AIM2 promoted RCC progression and sunitinib resistance through FOXO3a-ACSL4 axis-regulated ferroptosis, which could provide new ideas and therapeutic targets for RCC diagnosis and treatment.

Keywords: ACSL4; Absent in melanoma2; Ferroptosis; Renal cell carcinoma; Sunitinib resistance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Renal Cell* / drug therapy
Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / metabolism
Cell Line, Tumor
DNA-Binding Proteins
Drug Resistance, Neoplasm / genetics
Ferroptosis* / genetics
Humans
Kidney Neoplasms* / drug therapy
Kidney Neoplasms* / genetics
Kidney Neoplasms* / metabolism
Melanoma*
Sunitinib / pharmacology
Sunitinib / therapeutic use

Substances

Sunitinib
AIM2 protein, human
DNA-Binding Proteins