TAB182 regulates glycolytic metabolism by controlling LDHA transcription to impact tumor radiosensitivity
Shi Chen1,2, Da-Fei Xie2, Saiyu Li2,3
1School of Public Health, Hengyang Medical School, University of South China, Hengyang, Hunan Province, 421001, P. R. China.
Abstract:
Metabolic reprogramming, a hallmark of cancer, is closely associated with tumor development and progression. Changes in glycolysis play a crucial role in conferring radiation resistance to tumor cells. How radiation changes the glycolysis status of cancer cells is still unclear. Here we revealed the role of TAB182 in regulating glycolysis and lactate production in cellular response to ionizing radiation. Irradiation can significantly stimulate the production of TAB182 protein, and inhibiting TAB182 increases cellular radiosensitivity. 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. Moreover, knocking down TAB182 reverses radiation-induced metabolic changes, such as radioresistant-related lactate production. TAB182 is necessary for activating LDHA transcription by affecting transcription factors SP1 and c-MYC; its knockdown attenuates the upregulation of LDHA by radiation, subsequently suppressing lactate production. Targeted suppression of TAB182 significantly enhances the sensitivity of murine xenograft tumors to radiotherapy. These findings advance our understanding of glycolytic metabolism regulation in response to ionizing radiation, which may offer significant implications for developing new strategies to overcome tumor radioresistance.
Insights
Researchers discovered that TAB182 protein promotes radiation resistance in cancer cells by increasing glycolysis and lactate production. Inhibiting TAB182 enhances radiosensitivity, offering a potential strategy to improve radiotherapy outcomes.
Area of Science:
- Oncology
- Cancer Metabolism
- Radiation Biology
Background:
- Metabolic reprogramming is a key feature of cancer, influencing tumor growth and progression.
- Glycolysis alterations are critical for cancer cell radiation resistance, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of TAB182 in regulating glycolysis and lactate production in response to ionizing radiation.
- To determine if targeting TAB182 can overcome tumor radioresistance.
Main Methods:
- Irradiation of cancer cells and measurement of TAB182 protein levels.
- TAB182 knockdown experiments and analysis of metabolic changes (lactate, pyruvate, ATP).
- Investigation of TAB182's effect on LDHA transcription factors (SP1, c-MYC) and in vivo studies using murine xenograft models.
Main Results:
- Irradiation significantly increases TAB182 protein production.
- TAB182 knockdown decreases lactate production, increases pyruvate and ATP levels, and reverses radiation-induced metabolic changes.
- TAB182 is essential for radiation-induced LDHA transcription activation via SP1 and c-MYC.
- Targeting TAB182 enhances tumor radiosensitivity in vivo.
Conclusions:
- TAB182 plays a critical role in regulating cancer cell glycolysis and lactate production in response to ionizing radiation.
- Inhibiting TAB182 resensitizes tumors to radiotherapy by suppressing metabolic adaptation.
- Targeting TAB182 represents a promising strategy for overcoming tumor radioresistance.
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