Cyclophilin B induces chemoresistance by degrading wild-type p53 via interaction with MDM2 in colorectal cancer
Cyclophilin B induces chemoresistance by degrading wild-type p53 via interaction with MDM2 in colorectal cancer
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DOI：
10.1002/path.5107
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发表时间：
2018-09-01
影响因子：
7.3
通讯作者：
Kim, Sung Soo
中科院分区：
文献类型：
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作者：
Choi, Tae Gyu;Minh Nam Nguyen;Kim, Sung Soo
结直肠癌（CRC）是全球癌症相关死亡的主要原因之一。化疗耐药性是影响结直肠癌有效治疗的主要问题。在这里，我们研究了肽基脯氨酰异构酶B（PPIB;亲环素B，CypB）调节CRC化疗耐药性的机制。我们发现CypB是一种新的野生型p53（p53 WT）诱导型基因，但在奥沙利铂治疗反应中是p53 WT的负调节因子。CypB的过表达缩短了p53 WT的半衰期并抑制了CRC细胞中奥沙利铂诱导的细胞凋亡，而CypB的敲低延长了p53 WT的半衰期并刺激了p53 WT依赖性细胞凋亡。CypB直接与MDM 2相互作用，并增强MDM 2依赖性p53 WT泛素化和降解。此外，我们使用生物信息学分析坚定地验证了CypB的过表达与CRC进展和化疗耐药性的不良预后相关。因此，我们提出了一种新的机制，化疗耐药引起的过度表达CypB，这可能有助于开发新的抗癌药物。我们还建议CypB可用作CRC患者的预测生物标志物。版权所有（c）2018大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Chemoresistance is a major problem for effective therapy in CRC. Here, we investigated the mechanism by which peptidylprolyl isomerase B (PPIB; cyclophilin B, CypB) regulates chemoresistance in CRC. We found that CypB is a novel wild-type p53 (p53WT)-inducible gene but a negative regulator of p53WT in response to oxaliplatin treatment. Overexpression of CypB shortens the half-life of p53WT and inhibits oxaliplatin-induced apoptosis in CRC cells, whereas knockdown of CypB lengthens the half-life of p53WT and stimulates p53WT-dependent apoptosis. CypB interacts directly with MDM2, and enhances MDM2-dependent p53WT ubiquitination and degradation. Furthermore, we firmly validated, using bioinformatics analyses, that overexpression of CypB is associated with poor prognosis in CRC progression and chemoresistance. Hence, we suggest a novel mechanism of chemoresistance caused by overexpressed CypB, which may help to develop new anti-cancer drugs. We also propose that CypB may be utilized as a predictive biomarker in CRC patients. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.