The essential role of TAp73 in bortezomib-induced apoptosis in p53-deficient colorectal cancer cells.
The essential role of TAp73 in bortezomib-induced apoptosis in p53-deficient colorectal cancer cells.
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DOI：
10.1038/s41598-017-05813-z
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发表时间：
2017-07-14
影响因子：
4.6
通讯作者：
Cheng X
中科院分区：
文献类型：
--
作者：
Dabiri Y;Kalman S;Gürth CM;Kim JY;Mayer V;Cheng X
肿瘤抑制基因 p53 的突变是结直肠癌 (CRC) 中发生率最高的事件之一。此类突变已被证明会影响癌细胞对化疗药物的敏感性。然而，它们对蛋白酶体抑制剂硼替佐米功效的影响仍然存在争议。因此，我们重新评估了硼替佐米在 CRC 细胞系 HCT116 wt（野生型）及其 p53−/− 克隆中的毒性。在 p53 缺失细胞中观察到对硼替佐米治疗的短暂耐药性，随后伴随着 TAp73（p53 同源物 p73 的同种型）水平的增加和核易位，以及诱导细胞凋亡。使用 CRISPR/Cas9 敲低 p53−/− 细胞中的 p73 显着延长了耐药性的持续时间。此外，在携带突变p53的HT-29细胞中也观察到了类似的结果，但在表达功能性p53的人成纤维细胞中却没有观察到类似的结果。因此，我们的结果清楚地表明，在硼替佐米诱导的p53缺陷或突变细胞凋亡中，TAp73可以替代p53，这表明TAp73可能是治疗结直肠癌的潜在治疗靶点，特别是那些缺乏功能性p53的结直肠癌。
Mutations in the tumor suppressor p53 are among the most highly occurring events in colorectal cancer (CRC). Such mutations have been shown to influence the sensitivity of cancer cells to chemotherapeutic agents. However their impact on the efficacy of the proteasomal inhibitor bortezomib remains controversial. We thus re-evaluated the toxicity of bortezomib in the CRC cell lines HCT116 wt (wild-type) and its p53−/− clone. Transient resistance to bortezomib treatment was observed in p53-null cells that was later accompanied by an increase in levels and nuclear translocation of TAp73, an isoform of the p53-homologue p73, as well as induction of apoptosis. Knockdown of p73 in p53−/− cells using CRISPR/Cas9 significantly prolonged the duration of resistance. Moreover, similar results were observed in HT-29 cells carrying mutated p53, but not human fibroblasts with expression of functional p53. Thus, our results clearly demonstrated that TAp73 served as a substitute for p53 in bortezomib-induced apoptosis in p53-deficient or mutated cells, implicating that TAp73 could be a potential therapeutic target for treatment of CRCs, in particular those lacking functional p53.
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影响因子：
37.3
作者：
Cheng X;Holenya P;Can S;Alborzinia H;Rubbiani R;Ott I;Wölfl S
通讯作者：
Wölfl S
影响因子：
64.8
作者：
Liu, Yunhua;Zhang, Xinna;Lu, Xiongbin
通讯作者：
Lu, Xiongbin
影响因子：
11.8
作者：
Lenz, HJ
通讯作者：
Lenz, HJ
影响因子：
3.5
作者：
Cheng, Xinlai;Merz, Karl-Heinz;Eisenbrand, Gerhard
通讯作者：
Eisenbrand, Gerhard
影响因子：
12.4
作者：
MacLaren, AP;Chapman, RS;Watson, CJ
通讯作者：
Watson, CJ