目的:大多数透明细胞肾细胞癌(ccRCC)具有功能失调的vonHippel-Lindau肿瘤抑制蛋白(VHL)。缺氧诱导因子1和2α(HIF1α和HIF2α)在功能失调的VHLcccRCC中积累,并上调血管内皮生长因子(VEGF)途径和肿瘤血管生成。最近,Pimitespib(PIM),一种有效的ATP竞争性热休克蛋白90(HSP90)抑制剂,已开发。PIM下调HIF的表达,ccRCC进展中的关键蛋白,具有抗血管生成作用。本研究旨在探讨PIM在ccRCC中的有效性及其潜在机制。
方法:使用ccRCC细胞系评估PIM对ccRCC的功效和机制。
结果:PIM通过下调下游信号通路中的VEGFR2、磷酸化VEGFR2和蛋白水平来抑制VEGFR通路。PIM抑制ccRCC细胞系的生长。此外,PIM抑制HIF1α,HIF2α,和VEGF表达,这表明PIM除了抑制VEGFR途径外,还可以抑制血管生成。
结论:PIM提供了治疗ccRCC的新方法,并为未来的临床策略提供了希望。需要进一步的体内和临床研究来阐明PIM和ccRCC的作用之间的详细关系。
OBJECTIVE: Most clear cell renal cell carcinomas (ccRCCs) have a dysfunctional von Hippel-Lindau tumor suppressor protein (VHL). Hypoxia-inducible factors 1 and 2 alpha (HIF1α and HIF2α) accumulate in ccRCC with dysfunctional VHL and up-regulate the vascular endothelial growth factor (VEGF) pathway and tumor angiogenesis. Recently, pimitespib (PIM), a potent ATP-competitive inhibitor of heat shock protein 90 (HSP90), was developed. PIM down-regulates the expression of HIF, a key protein in ccRCC progression, with anti-angiogenic effects. This study aimed to examine the effectiveness of PIM in ccRCC and the underlying mechanisms.
METHODS: The efficacy and mechanism of PIM against ccRCCs was evaluated using ccRCC cell lines.
RESULTS: PIM inhibited the VEGFR pathway by down-regulating VEGFR 2, phosphorylated VEGFR 2, and protein levels in downstream signaling pathways. The growth of ccRCC cell lines was inhibited by PIM. Furthermore, PIM inhibits HIF1α, HIF2α, and VEGF expression, suggesting that PIM may suppress angiogenesis in addition to the VEGFR pathway.
CONCLUSIONS: PIM provides a novel approach for treating ccRCC and holds promise for future clinical strategies. Further in vivo and clinical research is required to elucidate the detailed relationship between the effects of PIM and ccRCC.