TY - JOUR
T1 - Novel cooperative pathway of c-Myc and Furin, a pro-protein convertase, in cell proliferation as a therapeutic target in ovarian cancers
AU - Hasegawa-Minato, Junko
AU - Toyoshima, Masafumi
AU - Ishibashi, Masumi
AU - Zhang, Xuewei
AU - Shigeta, Shogo
AU - Grandori, Carla
AU - Kitatani, Kazuyuki
AU - Yaegashi, Nobuo
N1 - Funding Information:
This study was supported in part by the JSPS Grants-in-Aids for Scientific Research (16K11125 to K.K., 24390375 to N.Y. and 26462509 to M.T.). Daiichi
Funding Information:
This study was supported in part by the JSPS Grants-in-Aids for Scientific Research (16K11125 to K.K., 24390375 to N.Y. and 26462509 to M.T.). Daiichi Sankyo CO., LTD. has supported this study by the TaNeDS (Take a New challenge for Drug diScovery) program. We also thank the laboratory members of the Departments of Obstetrics and Gynecology (Tohoku University, Sendai, Japan) for critical discussion.
Publisher Copyright:
© Hasegawa-Minato et al.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Furin
KW - Notch1
KW - Ovarian cancer
KW - Synthetic lethal
KW - c-Myc
UR - http://www.scopus.com/inward/record.url?scp=85040191081&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040191081&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.23322
DO - 10.18632/oncotarget.23322
M3 - Article
AN - SCOPUS:85040191081
VL - 9
SP - 3483
EP - 3496
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 3
ER -