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Novel cooperative pathway of c-Myc and Furin, a pro-protein convertase, in cell proliferation as a therapeutic target in ovarian cancers
- Source :
- Oncotarget
- Publication Year :
- 2017
-
Abstract
- c-Myc is a master regulator of various oncogenic functions in many types of human cancers. However, direct c-Myc-targeted therapy has not been successful in the clinic. Here, we explored a novel therapeutic target, which shows synthetic lethality in c-Myc-driven ovarian cancers, and examined the molecular mechanism of the synthetic lethal interaction. By high throughput siRNA screening with a library of 6,550 genes, Furin, a pro-protein convertase, was identified as the top hit gene. Furin inhibition by siRNA or a Furin inhibitor significantly suppressed cell proliferation in high c-Myc-expressing ovarian cancer cells compared with low c-Myc-expressing cells. Conversely, Furin overexpression in the presence of high c-Myc significantly promoted cell proliferation compared with only c-Myc or Furin overexpression. Notch1, one of the Furin substrates, was upregulated by c-Myc, and Notch1 cleaved by Furin increased cell proliferation of high c-Myc-expressing ovarian cancer cells. Notch1 was involved in the cooperative pathway of c-Myc and Furin in cell proliferation. In clinical ovarian cancer specimens, co-expression of c-Myc and Furin correlated with poor survival. In conclusion, we found that c-Myc cooperates with Furin to promote cell proliferation. Furin may be a promising therapeutic target in c-Myc-driven ovarian cancer.
- Subjects :
- 0301 basic medicine
animal structures
viruses
Synthetic lethality
Pro protein
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
medicine
Gene
Furin
Notch1
biology
Cell growth
Master regulator
medicine.disease
030104 developmental biology
c-Myc
ovarian cancer
Oncology
synthetic lethal
030220 oncology & carcinogenesis
embryonic structures
Cancer research
biology.protein
Ovarian cancer
Research Paper
Subjects
Details
- ISSN :
- 19492553
- Volume :
- 9
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....999ce83c2327763d2ee3299e7b83c960