FBXW7 modulates malignant potential and cisplatin-induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1.

Abstract

The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease-free and overall survival were significantly worse in the low-FBXW7 group than in the high-FBXW7 group (P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease-free (P = .006) and overall (P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self-renewal. Interestingly, when cells were stimulated with cis-diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7-mediated ubiquitylation is context-dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1.

• Authors: Akiko Mori, Kunihiro Masuda, Hideo Ohtsuka, Masahiro Shijo, Kyohei Ariake, Koji Fukase, Naoaki Sakata, Masamichi Mizuma, Takanori Morikawa, Hiroki Hayashi, Kei Nakagawa, Fuyuhiko Motoi, Takeshi Naitoh, Fumiyoshi Fujishima, Michiaki Unno
• Journal: Cancer science (Cancer Sci) Vol. 109 Issue 12 Pg. 3883-3895 (Dec 2018) ISSN: 1349-7006 [Electronic] England
• PMID: 30302867 (Publication Type: Journal Article)
• Copyright: © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• F-Box-WD Repeat-Containing Protein 7
• FBXW7 protein, human
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• NOTCH1 protein, human
• Receptor, Notch1
• Cisplatin

Topics

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cholangiocarcinoma (metabolism)
• Cisplatin (pharmacology)
• Disease Progression
• Down-Regulation
• F-Box-WD Repeat-Containing Protein 7 (metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Middle Aged
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Prognosis
• Receptor, Notch1 (metabolism)
• Survival Analysis