Medical Imaging Center, Taihe Hospital, No.32 Renmin South Road, Shiyan 442000, Hubei Province, China.
Biol Chem. 2021 Aug 9;402(10):1247-1256. doi: 10.1515/hsz-2021-0280. Print 2021 Sep 27.
Renal cell carcinoma (RCC) is the third most frequent malignancy within urological oncology. Sunitinib has been used as the standard of treatment for first-line RCC therapy. Understanding mechanisms of sunitinib resistance in RCC cell is important for clinical therapy and drug development. We established sunitinib resistant RCC cells by treating cells with increasing concentrations of sunitinib and named resistant cells as RCC/SR. Lefty A, an important embryonic morphogen, was increased in RCC/SR cells. Targeted inhibition of Lefty via its siRNAs restored the sensitivity of renal resistant cells to sunitinib treatment. It was due to that si-Lefty can decrease the expression of interleukin-8 (IL-8) in RCC/SR cells. Knockdown of IL-8 abolished Lefty-regulated sunitinib sensitivity of RCC cells. Mechanistically, Lefty can regulate IL-8 transcription via activation of p65, one major transcription factor of IL-8. Collectively, our present revealed that Lefty A can regulate sunitinib sensitivity of RCC cells of via NF-κB/IL-8 signals. It indicated that targeted inhibition of Lefty might be a potent approach to overcome sunitinib resistance of RCC.
肾细胞癌（RCC）是泌尿肿瘤学中第三大常见恶性肿瘤。舒尼替尼已被用作 RCC 一线治疗的标准治疗方法。了解 RCC 细胞中舒尼替尼耐药的机制对于临床治疗和药物开发非常重要。我们通过用递增浓度的舒尼替尼处理细胞来建立舒尼替尼耐药的 RCC 细胞，并将耐药细胞命名为 RCC/SR。Lefty A 是一种重要的胚胎形态发生素，在 RCC/SR 细胞中增加。通过其 siRNAs 靶向抑制 Lefty 可恢复肾耐药细胞对舒尼替尼治疗的敏感性。这是因为 si-Lefty 可以降低 RCC/SR 细胞中白细胞介素 8（IL-8）的表达。IL-8 的敲低消除了 Lefty 调节的 RCC 细胞对舒尼替尼的敏感性。从机制上讲，Lefty 可以通过激活 IL-8 的主要转录因子之一 p65 来调节 IL-8 的转录。总之，我们目前的研究表明，Lefty A 可以通过 NF-κB/IL-8 信号调节 RCC 细胞对舒尼替尼的敏感性。这表明靶向抑制 Lefty 可能是克服 RCC 舒尼替尼耐药的有效方法。
