Dataset Information

AKT1 confers tumor resistance to cuproptosis by phosphorylating FDX1

ABSTRACT: Cuproptosis, a recently defined copper-dependent cell death, remains largely unexplored in tumor therapies, particularly in breast cancer. Our study demonstrates that triple-negative breast cancer (TNBC) bears a relative elevated copper levels and exhibit resistance to cuproptosis. Mechanistically, cooper activates AKT1 signaling pathway, which inhibits cuproptosis by directly phosphorylating ferredoxin-1 (FDX1), a key regulator involved in cuproptosis. AKT1-mediated FDX1 phosphorylation abrogates FDX1-induced cuproptosis and aerobic respiration, accompanied by promoting glycolysis. Consequently, combination of AKT1 inhibitors MK2206 and the copper ionophore elesclomol (ES) synergistically inhibits TNBC tumorigenesis both in vitro and in vivo. In summary, our findings uncover a critical mechanism underlying TNBC resistance to cuproptosis and propose a potential therapeutic approach for TNBC.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: sun zicheng

LAB HEAD: Zicheng Sun

PROVIDER: PXD058176 | Pride | 2025-05-07

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Homo_sapiens_SP_uniprot_20230307.fasta	Fasta
	Y480A_FAIMS_LFQ_PMJ291_MSMSSpectrumInfo.txt	Txt
	Y480A_FAIMS_LFQ_PMJ291_PSMs.txt	Txt
	Y480A_FAIMS_LFQ_PMJ291_PeptideGroups.txt	Txt
	Y480A_FAIMS_LFQ_PMJ291_Proteins.txt	Txt

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Publications

AKT1 Phosphorylates FDX1 to Promote Cuproptosis Resistance in Triple-Negative Breast Cancer.

Sun Zicheng Z Xu Huazhen H Lu Guanming G Yang Ciqiu C Gao Xinya X Zhang Jing J Liu Xin X Chen Yongcheng Y Wang Kun K Guo Jianping J Li Jie J

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20250220 17

Cuproptosis, a recently defined copper-dependent cell death pathway, remains largely unexplored in tumor therapies, particularly in breast cancer. This study demonstrates that triple-negative breast cancer (TNBC) bears a relatively elevated copper levels and exhibits resistance to cuproptosis. Mechanistically, copper activates the AKT signaling pathway, which inhibits ferredoxin-1 (FDX1), a key regulator of cuproptosis. AKT1-mediated FDX1 phosphorylation not only abrogates FDX1-induced cuproptos ...[more]

PMID: 39976173

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Project description:Phosphorylation is well-known in regulating various biological processes. However, comprehensively phosphoproteomic profiling in the termination of liver regeneration (LR) is still missing. Here, we used TMT labeling coupled with phosphopeptides enrichment and 2D LC-MS/MS analysis to establish a global phosphoproteomic map in mice liver at day 5 after partial hepatectomy. Altogether, 619 phosphorylation sites in 437 proteins were significantly up-regulated and 503 phosphorylation sites in 358 proteins were down-regulated. The differentially phosphorylated proteins were further classified according to their biological process, cellular components, molecular function and subcellular localization. KEGG pathway analysis showed that they mainly participate in metabolic pathways, DNA replication, tight junction and focal adhesion. Motif analysis of the identified phosphorylation sites has revealed a diverse array of consensus sequences, suggesting multiple kinase families such as MAPK, PKA/PKC, CaMK-II, CKII and CDK, may be involved in the termination of LR. Finally, several differentially phosphorylated proteins were validated by Co-immunoprecipitation and Western blot. Taken together, our data unravels the first comprehensive phosphoproteomic map in the termination of liver regeneration in mice, which greatly expands our knowledge in the complicate regulation of this process and provides new directions on the treatment of liver cancer using liver resection and donor liver transplantation. Biological significance: The novelty of this study is that we have established for the first time a global phosphoproteomic map in mice liver at day 5 after partial hepatectomy, which represents the termination of liver regeneration. Altogether, 9,775 phosphorylation sites in 3,458 proteins were identified, among which 7,738 phosphorylation site in 2,971 proteins were quantified. KEGG pathway analysis demonstrates markedly metabolic reprograming in termination of LR, which is further validated by selected validation of several differentially phosphorylated metabolic enzymes such as PDHA, ACACA and FASN. The consistent high phosphorylation of PDHA in the first 4 days and its rapidly decreased phosphorylation at day 5 after PH might be a key signal in controlling the switch between glycolysis and oxidative