Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1.
Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1.
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DOI：
10.1126/scisignal.aac5418
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发表时间：
2015-10-06
影响因子：
7.3
通讯作者：
Shah YM
中科院分区：
文献类型：
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作者：
Zhang H;Ramakrishnan SK;Triner D;Centofanti B;Maitra D;Győrffy B;Sebolt-Leopold JS;Dame MK;Varani J;Brenner DE;Fearon ER;Omary MB;Shah YM
yes相关蛋白1 （YAP1）是Hippo信号通路中的转录辅激活因子。YAP1-活性的增加促进肿瘤的生长，包括结直肠癌（CRC）。维替波芬是一种增强光疗以治疗新生血管性黄斑变性的药物，是YAP1的抑制剂。在这里，我们发现，在遗传或化学诱导的CRC小鼠模型、患者来源的异种移植和CRC肠样模型中，维替泊芬抑制肿瘤生长独立于其对YAP1或相关蛋白TAZ的影响。相反，维替波芬在体内表现出杀死肿瘤细胞的选择性，部分原因是通过损害高分子量寡聚化蛋白的整体清除，特别是p62（参与自噬的一种sequestome）和STAT3（一种转录因子）。维替波芬抑制细胞因子诱导的STAT3活性和细胞增殖，降低培养的结直肠癌细胞的存活率。尽管体内正常细胞中椎泊芬的积累程度大于肿瘤细胞，但培养细胞的实验表明，正常细胞通过自噬和蛋白酶体途径有效地清除了椎泊芬诱导的蛋白低聚物。在缺氧或营养剥夺的条件下培养CRC细胞（模拟典型的CRC微环境）会损害蛋白质低聚物的清除并导致细胞死亡；而在常氧或充满葡萄糖的条件下培养细胞，在维替泊芬的存在下，可以保护细胞的活力和增殖。此外，即使在缺乏YAP1的情况下，verteporfin也能抑制其他癌细胞系的增殖，这表明verteporfin可能对多种类型的实体癌有效。
Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1- activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. Here, we found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetic or chemical-induced mouse models of CRC, in patient-derived xenografts and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viabilty of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells in hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death; whereas culturing cells in normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers.