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Published on: July 21, 2018
High-dose radiation-resistant lung cancer cells stored many functional lipid drops through JAK2/p-STAT3/FASN pathway
Ting Yang1, Simiao Qiao1, Xiaoxia Zhu2
1Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou, 510515, Guangdong, China.
Background:
The understanding of radiation resistance is still unclear. This study aims to explore the new mechanism of radiation resistance in lung cancer from the perspective of lipid metabolism.
Methods:
Oil red O was used to detect the amount of lipid droplets in high-dose radiation-resistant lung cancer cells (HDRR-LCCs) and the primary lung cancer cells. Western blot analysis was used to determine the protein expression levels of key molecules related to de novo fatty acid synthesis and fatty acid transport. Orlistat was used to inhibit the de novo fatty acid synthesis. The prediction of the transcriptional regulators of fatty acid synthetase (FASN) was analyzed by bioinformatics. AZD-1480 was used to inhibit the JAK2/STAT3 pathway to observe its effects on FASN and intracellular lipid droplets. The regulation of the transcription factor p-STAT3 on the FASN gene was verified by Chip-qPCR. Finally, we used the public data of lung cancer patients to analyze the correlation between FASN and LPL gene expression with the prognosis.
Results:
There were more lipid drops in the HDRR-LCCs than in the primary lung cancer cells. HDRR-LCCs preferred de novo synthesis of fatty acids, and high expression of LPL homodimers indicated a high intake of extracellular fatty acids. The expression of FASN was increased in HDRR-LCCs compared with the primary lung cancer cells in a radiation-dose-dependent way, while LPL homodimers did not show such a trend. The lipid droplets, cell proliferation, and radiation resistance were decreased in HDRR-LCCs after orlistat treatment. Lipid droplets were significantly reduced, and the protein expression of FASN also decreased when using AZD-1480 to inhibit the JAK2/STAT3 pathway. The Chip-qPCR showed that p-STAT3 was the upstream regulator which binds to the promoter region of FASN. Survival analysis showed that high expression of the FASN gene was associated with a poor prognosis in lung cancer patients who received radiotherapy.
Conclusion:
Our studies discovered that lipids deposited in HDRR-LCCs were due to endogenous de novo fatty acids synthesis and exogenous lipids uptake. JAK2/p-TAT3/FASN could be used as promising targets for radiotherapy sensitization. Our study provided a new theoretical basis for studying the mechanism of radiation resistance in lung cancer.
Insights
Lung cancer cells resistant to radiation accumulate lipids through both internal synthesis and external uptake. Targeting the JAK2/p-STAT3/FASN pathway can enhance radiotherapy effectiveness by reducing lipid accumulation.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Radiation resistance in lung cancer remains poorly understood.
- Lipid metabolism is increasingly recognized as a potential factor in cancer progression and treatment resistance.
Purpose of the Study:
- To investigate the role of lipid metabolism in the mechanism of radiation resistance in lung cancer.
- To identify potential therapeutic targets for sensitizing lung cancer to radiotherapy.
Main Methods:
- Quantification of lipid droplets using Oil red O staining.
- Western blot analysis of key proteins in fatty acid synthesis and transport.
- Inhibition of de novo fatty acid synthesis with Orlistat.
- Bioinformatic analysis of fatty acid synthetase (FASN) transcriptional regulators.
- Inhibition of the JAK2/STAT3 pathway with AZD-1480.
- Validation of transcription factor binding using Chip-qPCR.
- Correlation analysis of FASN and LPL gene expression with patient prognosis using public data.
Main Results:
- Radiation-resistant lung cancer cells (HDRR-LCCs) exhibit increased lipid droplets compared to primary cells.
- HDRR-LCCs show a preference for de novo fatty acid synthesis and high extracellular fatty acid uptake.
- FASN expression increased in HDRR-LCCs in a radiation-dose-dependent manner.
- Inhibition of de novo fatty acid synthesis (Orlistat) and JAK2/STAT3 pathway (AZD-1480) reduced lipid droplets, cell proliferation, and radiation resistance.
- p-STAT3 was identified as an upstream regulator of FASN.
- High FASN gene expression correlated with poor prognosis in lung cancer patients receiving radiotherapy.
Conclusions:
- Lipid accumulation in radiation-resistant lung cancer cells is driven by both endogenous fatty acid synthesis and exogenous lipid uptake.
- The JAK2/p-STAT3/FASN signaling pathway is a critical regulator of lipid metabolism and radiation resistance in lung cancer.
- Targeting the JAK2/p-STAT3/FASN pathway presents a promising strategy for enhancing radiotherapy sensitization in lung cancer.
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