Spermidine inactivates proteasome activity and enhances ferroptosis in prostate cancer.
10.1016/j.apsb.2025.02.023
- Author:
Dan FENG
1
;
Jian ZHANG
2
;
Huanmin NIU
2
;
Xiaoxue ZHENG
2
;
Mengqi JIA
2
;
Qiqi LU
2
;
Jing WANG
2
;
Wenxue GUO
2
;
Qi SUN
2
;
Huiqing YUAN
2
;
Hongxiang LOU
1
Author Information
1. Department of Natural Medicinal Chemistry and Pharmacognosy, School of Pharmacy, Qingdao University, Qingdao 266071, China.
2. Institute of Medical Sciences of the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
- Publication Type:Journal Article
- Keywords:
EIF5A;
Ferroptosis;
HMOX1;
NRF2;
Polyamines;
Prostate cancer;
Proteasome;
Spermidine
- From:
Acta Pharmaceutica Sinica B
2025;15(4):2095-2113
- CountryChina
- Language:English
-
Abstract:
The elevated polyamines, amine-rich molecules with diverse functions in pathophysiology processes, are implicated in contributing to tumorigenesis and progression. Whether and how they affect the efficacy of chemotherapy is incompletely understood. Our screening assays reveal that the supplement with a low dose of spermidine (Spd), one of the polyamines, enhances ferroptosis in prostate cancer cells as evidenced by increased lipid peroxidation and intracellular Fe2+ levels in vitro. Combination treatment with Spd and a low dose of ferroptosis inducer erastin synergistically augments anti-tumor efficacy with undetectable toxicity in mice. Analysis of RNA-seq data indicates that heme oxygenase 1 (HMOX1), an enzyme that catalyzes the cleavage of heme to release Fe2+, is significantly upregulated in response to Spd and erastin cotreatment. Spd mediated the hypusine modification of the eukaryotic initiation factor 5A (EIF5A) promotes the translation of the nuclear factor erythroid 2-related factor 2 (NRF2), subsequently leading to elevation of HMOX1. Moreover, Spd and erastin significantly inhibit proteasome activity which results in a decrease in proteasomal degradation of NRF2, although many proteasome-related genes are induced either by Spd or Spd plus erastin. Thus, in addition to its pro-oncogenic activity, the supplement of Spd improves antitumor activity in combination with ferroptosis inducers and offers an optional approach to cancer treatment.
