TAB182 Regulates Glycolytic Metabolism by Controlling LDHA Transcription to Impact Tumor Radiosensitivity

Abstract

Abstract Background Metabolic reprogramming is a significant characteristic of cancer cells, and closely associated with the resistance of tumors to radiotherapy. Metabolic change involves multiple pathways, with much yet to be understood. This study aims to identify key factors influencing tumor metabolism, potentially aiding in combating radiation resistance in cancer therapy. Method Proteomic analysis elucidated the role of TAB182 in cellular processes. Glycolysis-related markers (lactate, pyruvate, and ATP) were measured using specific assays. Metabolic-related mRNA and protein expression was evaluated using qPCR and Western blotting experiments. Transcriptional activity was quantified with dual-luciferase reporter assays, and tumor cell radiation sensitivity was determined through clonogenic assays and nude mouse xenograft models. Results Ionizing radiation (IR) significantly increases TAB182 expression, and knocking down TAB182 enhances cancer cells' sensitivity to IR. Proteomic analysis indicated that TAB182 influences several vital biological processes, including multiple metabolic pathways. Knockdown of TAB182 results in decreased lactate production and increased pyruvate and ATP levels in cancer cells. Additionally, knocking down TAB182 reverses radiation-induced metabolic changes, such as radioresistant-related lactate production. Further investigation reveals TAB182's necessity for activating LDHA transcription, with its knockdown attenuating the upregulation of LDHA by IR, subsequently suppressing lactate production. Subsequent studies reveal that TAB182 controls LDHA expression by affecting transcription factors SP1 and c-MYC. Targeted suppression of TAB182 significantly enhances the sensitivity of murine xenograft tumors to radiotherapy. Conclusion The study unveils a novel role of TAB182 in glucose metabolism by controlling LDHA transcription, potentially affecting IR-induced metabolic reprogramming in tumor cells during radiotherapy. Targeting TAB182 may offer significant implications for developing therapeutic strategies in tumor radiosensitization.