Cyclophilin B induces chemoresistance by degrading wild‐type p53 via interaction with MDM2 in colorectal cancer |
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| Authors: | Jieun Kim Yong Hwa Jo Miran Jang Ngoc Ngo Yen Nguyen Hyeong Rok Yun Wonchae Choe Insug Kang Joohun Ha Dean G Tang Sung Soo Kim |
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| Affiliation: | 1. Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea;2. Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea;3. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York, USA |
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| Abstract: | 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 © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
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| Keywords: | chemoresistance colorectal cancer cyclophilin B oxaliplatin wild‐type p53 PPIB |
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