Novel cooperative pathway of c-Myc and Furin, a pro-protein convertase, in cell proliferation as a therapeutic target in ovarian cancers

作者：Hasegawa-Minato Junko; Toyoshima Masafumi^*; Ishibashi Masumi; Zhang Xuewei; Shigeta Shogo; Grandori Carla; Kitatani Kazuyuki^*; Yaegashi Nobuo

来源：Oncotarget, 2018, 9(3): 3483-3496.

DOI：10.18632/oncotarget.23322

• c-Myc
• Furin
• ovarian cancer
• synthetic lethal
• Notch1

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.

• 出版日期2018-1-9