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

Junko Hasegawa-Minato, Masafumi Toyoshima, Masumi Ishibashi, Xuewei Zhang, Shogo Shigeta, Carla Grandori, Kazuyuki Kitatani, Nobuo Yaegashi

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3483-3496
Number of pages14
JournalOncotarget
Volume9
Issue number3
DOIs
Publication statusPublished - 2018

Keywords

  • Furin
  • Notch1
  • Ovarian cancer
  • Synthetic lethal
  • c-Myc

ASJC Scopus subject areas

  • Oncology

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