AKR1B10 mediates glycolysis and proliferation in breast cancer via the IGF2R-PGK1-H4K12la-mTOR signaling axis

The metabolic landscape of breast cancer is intricately associated with patient outcomes, with metabolic reprogramming serving as a crucial determinant. Nevertheless, the precise relationship between AKR1B10, a metabolic enzyme, and metabolism has remained elusive. The expression and clinical relevance of AKR1B10 in breast cancer tissues and cell lines were examined through a comprehensive approach that integrated bioinformatics, metabolomics, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis. The impact of AKR1B10 on breast cancer metabolism was investigated through the implementation of gain- and loss-of-function experiments, conducted both in vitro and in vivo. This was complemented by the utilization of mass spectrometry and glucose metabolism analysis. To elucidate the potential underlying mechanisms, co-immunoprecipitation (Co-IP), RNA sequencing (RNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) techniques were employed. This study demonstrated that aberrant overexpression of AKR1B10 is essential for tumor cell proliferation and the activation of the Warburg effect in breast cancer. The findings revealed that AKR1B10 functions as a bridge linking the insulin-like growth factor 2 receptor (IGF2R) and phosphoglycerate kinase 1 (PGK1), resulting in the phosphorylation of PGK1 at Y324 through IGF2R. This activation ultimately enhanced the Warburg effect and lactate production, promoted dynamic lactylation of H4K12 (H4K12la, histone H4 lysine 12 lactylation), and led to the transcriptional activation of mTOR, which promoted breast cell proliferation. The present study has identified a novel mechanism involving the IGF2R-AKR1B10-PGK1-H4K12la-mTOR signaling axis, which has been demonstrated to exacerbate the Warburg effect and promote tumorigenesis in breast cancer. AKR1B10 knockdown or the combination of the AKR1B10 inhibitor oleanolic acid (OA) with the glycolysis inhibitor D-arabino-2-deoxyhexose (2-DG) were found to inhibit this axis, thereby reprogramming the metabolism of breast cancer cells and suppressing proliferation. These findings underscore the critical role of AKR1B10 in reprogramming breast cancer cells’ metabolism, and provides a rationale for the development of a novel therapeutic strategy for the treatment of breast cancer.