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TBK1 Reprograms Metabolism in Breast Cancer: An Integrated Omics Approach.

TBK1 Reprograms Metabolism in Breast Cancer: An Integrated Omics Approach.

Authors :
Maan M
Jaiswal N
Liu M
Saavedra HI
Chellappan SP
Dutta M
Source :
Journal of proteome research [J Proteome Res] 2025 Jan 03; Vol. 24 (1), pp. 121-133. Date of Electronic Publication: 2024 Dec 13.
Publication Year :
2025

Abstract

Metabolic rewiring is required for cancer cells to survive in harsh microenvironments and is considered to be a hallmark of cancer. Specific metabolic adaptations are required for a tumor to become invasive and metastatic. Cell division and metabolism are inherently interconnected, and several cell cycle modulators directly regulate metabolism. Here, we report that TBK1, which is a noncanonical IKK kinase with known roles in cell cycle regulation and TLR signaling, affects cellular metabolism in cancer cells. While TBK1 is reported to be overexpressed in several cancers and its enhanced protein level correlates with poor prognosis, the underlying molecular mechanism involved in the tumor-promoting role of TBK1 is not fully understood. In this study, we show a novel role of TBK1 in regulating cancer cell metabolism using combined metabolomics, transcriptomics, and pharmacological approaches. We find that TBK1 mediates the regulation of nucleotide and energy metabolism through aldo-keto reductase B10 (AKRB10) and thymidine phosphorylase (TYMP) genes, suggesting that this TBK1-mediated metabolic rewiring contributes to its oncogenic function. In addition, we find that TBK1 inhibitors can act synergistically with AKRB10 and TYMP inhibitors to reduce cell viability. These findings raise the possibility that combining these inhibitors might be beneficial in combating cancers that show elevated levels of TBK1.

Details

Language :
English
ISSN :
1535-3907
Volume :
24
Issue :
1
Database :
MEDLINE
Journal :
Journal of proteome research
Publication Type :
Academic Journal
Accession number :
39670797
Full Text :
https://doi.org/10.1021/acs.jproteome.4c00530