The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro
The Efficacy of Sunitinib Treatment of Renal Cancer Cells Is Associated with the Protein PHAX In Vitro
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DOI：
10.3390/biology9040074
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发表时间：
2020-04
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通讯作者：
R. Al‐Lamki;N. Hudson;J. Bradley;A. Warren;T. Eisen;S. Welsh;Antony C. P. Riddick;Fiach C. O’Mahony;A. Turnbull;T. Powles;A. Reverter;D. Harrison;G. Stewart
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作者：
R. Al‐Lamki;N. Hudson;J. Bradley;A. Warren;T. Eisen;S. Welsh;Antony C. P. Riddick;Fiach C. O’Mahony;A. Turnbull;T. Powles;A. Reverter;D. Harrison;G. Stewart
抗血管生成药物，如多酪氨酸激酶抑制剂舒尼替尼，是转移性透明细胞肾细胞癌（ccRCC）的关键一线治疗药物，但其作用机制尚不完全清楚。在这里，我们采取步骤验证基于差异转录组网络分析的计算预测，磷酸化适配器RNA输出蛋白（PHAX）与舒尼替尼药物治疗相关。在患者组织样本上运行的调控影响因子差分网络算法表明，PHAX可能是通过改变全基因组网络连接的重要调控因子。患者肿瘤的免疫荧光染色显示PHAX强烈定位于微血管，这与舒尼替尼的抗血管生成作用一致。在正常肾组织中，PHAX蛋白丰度较低，但随着肿瘤分级而增加（G1 vs. G3/4; p < 0.01），这与可能在癌症进展中的作用一致。在器官培养中，ccRCC细胞的PHAX蛋白表达水平高于正常肾细胞，舒尼替尼使PHAX蛋白表达呈剂量依赖性增加（未处理vs. 100µM; p < 0.05）。在ccRCC器官培养模型中，PHAX敲低会影响舒尼替尼导致癌细胞死亡的能力（未治疗组与治疗组相比p < 0.0001），这表明PHAX在介导舒尼替尼疗效中发挥作用。
Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; p < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; p < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death (p < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.