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NGAL can alternately mediate sunitinib resistance in renal cell carcinoma
Dah-Shyong Yu1, Chia-Lun Wu2, Szu-Yuan Ping1
1Uro-Oncology Laboratory, Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Tainan, Taiwan, Republic of China.
Purpose:
Serum NGAL is highly expressed in patients with advanced renal cancer treated with sunitinib. We investigated the role of NGAL in sunitinib resistance in renal cell carcinoma to identify potential tactics to overcome it.
Materials And Methods:
NGAL expression was correlated with sunitinib sensitivity. Vascular endothelial growth factor related upstream Ras, Erk1/2 and STAT1 phosphorylation activity in Caki-1 and NGAL transfected Caki-1 cells after sunitinib treatment was analyzed using Western blot. NGAL and vascular endothelial growth factor-A interaction with sunitinib therapeutic efficacy was monitored in renal cell carcinoma tumor xenografted mice by tumor growth inhibition, serum NGAL and vascular endothelial growth factor-a levels, and microscopic examination of tumor microvascular density.
Results:
Sunitinib cytotoxicity in various renal cell carcinoma cell lines was reversibly related to NGAL expression. Sunitinib showed the lowest 50% inhibitory concentration (5.53 μM) in Caki-1 cells, which had the lowest NGAL expression of these renal cell carcinoma cell lines. After sunitinib treatment adding NGAL inhibited Ras and Erk1/2 phosphorylation but activated STAT1α phosphorylation in Caki-1 cells and Caki-1 cells transfected with NGAL. In a xenograft mouse model sunitinib significantly inhibited tumor growth in Caki-1 mice. NGAL transfected Caki-1 mice had higher serum NGAL and lower vascular endothelial growth factor-A than Caki-1 mice. Microvascular density was decreased in Caki-1 mice with sunitinib treatment.
Conclusions:
NGAL in tumor cells may show crosstalk with vascular endothelial growth factor-a and alternative activation in stimulating tumor growth during sunitinib treatment. It may become a therapeutic target to reverse sunitinib resistance in renal cell carcinoma.
Insights
Neutrophil gelatinase-associated lipocalin (NGAL) may drive resistance to sunitinib in renal cell carcinoma. Targeting NGAL could potentially overcome this resistance, improving treatment efficacy for advanced kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Serum NGAL is elevated in advanced renal cancer patients treated with sunitinib.
- Understanding NGAL's role in sunitinib resistance is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate the role of NGAL in mediating sunitinib resistance in renal cell carcinoma (RCC).
- To identify potential therapeutic targets for overcoming sunitinib resistance in RCC.
Main Methods:
- Correlated NGAL expression with sunitinib sensitivity in RCC cell lines.
- Analyzed signaling pathways (Ras, Erk1/2, STAT1) using Western blot.
- Evaluated sunitinib efficacy in a xenograft mouse model, assessing tumor growth, serum NGAL, VEGF-A, and microvascular density.
Main Results:
- Sunitinib cytotoxicity inversely correlated with NGAL expression; lower NGAL meant higher sensitivity.
- NGAL modulated Ras/Erk1/2 and STAT1 phosphorylation in response to sunitinib.
- In vivo, sunitinib inhibited tumor growth, and NGAL presence influenced serum markers and microvascular density.
Conclusions:
- NGAL may interact with VEGF-A and alternative pathways to promote tumor growth during sunitinib therapy.
- NGAL represents a potential therapeutic target to reverse sunitinib resistance in RCC.
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