Novel cooperative pathway of c-Myc and Furin, a pro-protein convertase, in cell proliferation as a therapeutic target in ovarian cancers
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Junko Hasegawa-Minato1, Masafumi Toyoshima1, Masumi Ishibashi1, Xuewei Zhang1, Shogo Shigeta1,3, Carla Grandori3,4, Kazuyuki Kitatani1,2 and Nobuo Yaegashi1
1Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan
2Tohoku Medical Megabank Organization, Tohoku University Graduate School of Medicine, Sendai, Japan
3Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
4SEngine Precision Medicine, Seattle, WA, USA
Masafumi Toyoshima , email: [email protected]
Kazuyuki Kitatani, email: [email protected]
Keywords: c-Myc; Furin; ovarian cancer; synthetic lethal; Notch1
Received: September 20, 2017 Accepted: November 16, 2017 Published: December 15, 2017
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.
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