ALOX5 Mediates Sunitinib Resistance in Renal Cell Carcinoma by Reprogramming Lipid Metabolism Through the P38/erk/pparα Axis.

OBJECTIVE:To investigate the molecular mechanisms of lipid metabolic reprogramming promoting tyrosine kinase inhibitors (TKIs) resistance in renal cell carcinoma (RCC). METHODS:To establish a sunitinib resistant renal cell carcinoma cell line (786O-R) and screen out arachidonic acid 5-lipoxygenase (ALOX5), a key gene regulating lipid metabolism, by transcriptome sequencing. To explore the expression of ALOX5 in TKI-resistant RCC tissues and cells, and the relationship between ALOX5 expression and the prognosis of RCC patients through databases and clinical samples. To explore the effect of ALOX5 on the malignant biological behavior of RCC cells and drug resistance to sunitinib in vitro. Transcriptome sequencing and molecular experiments were performed to explore the molecular mechanism of ALOX5 regulating lipid metabolism. The effect of ALOX5 inhibition on the tumorigenesis of 786O-R cell was investigated by animal experiments. RESULTS:ALOX5 is upregulated in TKI-resistant RCC tissues and cells. High ALOX5 expression is associated with poor prognosis of patients with RCC. Overexpression of ALOX5 can enhance the proliferation, migration, invasion and sunitinib resistance of 786O-R cell. ALOX5 promotes sunitinib resistance in 786O-R cell by regulating lipid metabolism through the p38/ERK/PPARα/CPT1A pathway. Inhibition of ALOX5 inhibited the growth of subcutaneous tumors and lung metastases in 786O-R cell. CONCLUSION:ALOX5 mediates sunitinib resistance in RCC by promoting lipid metabolism through the p38/ERK/PPARα/CPT1A pathway. Inhibition of ALOX5 may be a potential therapeutic target for intervention of metabolic abnormalities and overcoming resistance to targeted therapy in RCC.