LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.
LDL cholesterol counteracts the antitumour effect of tyrosine kinase inhibitors against renal cell carcinoma.
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DOI：
10.1038/bjc.2017.77
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发表时间：
2017-04-25
影响因子：
8.8
通讯作者：
Kolenko VM
中科院分区：
文献类型：
--
作者：
Naito S;Makhov P;Astsaturov I;Golovine K;Tulin A;Kutikov A;Uzzo RG;Kolenko VM
酪氨酸激酶抑制剂（TKI）治疗可显著提高肾细胞癌（RCC）患者的生存率。然而，约四分之一的RCC患者主要对TKI治疗无效。我们检测了用低密度脂蛋白（LDL）和/或TKI处理的RCC和内皮细胞的活力。接下来，我们验证了PI 3 K/AKT信号传导在LDL介导的TKI抗性中的潜在作用。最后，我们研究了高脂肪/高胆固醇饮食对RCC异种移植肿瘤对舒尼替尼的反应的影响。LDL胆固醇的添加增加了PI 3 K/AKT信号传导的激活，并损害了TKI对RCC和内皮细胞的抗肿瘤功效。此外，RCC异种移植肿瘤在喂食高脂肪/高胆固醇饮食的小鼠中抵抗TKI。肾肿瘤维持胆固醇稳态的能力可能是RCC患者TKI耐药的关键组成部分。
Treatment with tyrosine kinase inhibitors (TKIs) significantly improves survival of patients with renal cell carcinoma (RCC). However, about one-quarter of the RCC patients are primarily refractory to treatment with TKIs. We examined viability of RCC and endothelial cells treated with low-density lipoprotein (LDL) and/or TKIs. Next, we validated the potential role of PI3K/AKT signalling in LDL-mediated TKI resistance. Finally, we examined the effect of a high-fat/high-cholesterol diet on the response of RCC xenograft tumours to sunitinib. The addition of LDL cholesterol increases activation of PI3K/AKT signalling and compromises the antitumour efficacy of TKIs against RCC and endothelial cells. Furthermore, RCC xenograft tumours resist TKIs in mice fed a high-fat/high-cholesterol diet. The ability of renal tumours to maintain their cholesterol homoeostasis may be a critical component of TKI resistance in RCC patients.