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.
Highlights
C-Myc is one of the most commonly altered oncogenes in many types of human cancers
We focused on growth factors and their receptors, such as transforming growth factor (TGF)-β1–3, insulin-like growth factor (IGF)-1 and 2, insulin-like growth factor receptor (IGFR)-1, platelet-derived growth factor (PDGF)-A and -B, vascular endothelial growth factor (VEGF)-A–C, and Notch1–4, because Furin played an important role in cell proliferation in the presence of c-Myc (Figure 3B)
By high throughput functional siRNA screening, we identified Furin as a novel therapeutic target that shows a synthetic lethal interaction in c-Myc-driven ovarian cancer
Summary
C-Myc is one of the most commonly altered oncogenes in many types of human cancers It increases DNA synthesis, transcription, RNA processing, synthesis of ribosomal proteins, and regulates the activities of metabolic pathways. Some cancer cells depend on specific oncogenic pathways for their survival, so-called oncogene addiction [11] This phenomenon provides a rationale for molecular targeted therapy, such as the BCR-ABL (breakpoint cluster region protein-Abelson murine leukemia viral oncogene homolog 1) fusion gene in chronic myelogenous leukemia, EGFR (epidermal growth factor receptor) mutations and ALK (anaplastic lymphoma kinase) fusion in non-small cell lung carcinoma [12, 13]. We identified Furin, a calciumdependent serine protease that belongs to the pro-protein convertase family, as a novel therapeutic target that shows synthetic lethality in c-Myc-driven ovarian cancers by high throughput siRNA screening. We propose a novel cooperative pathway of c-Myc and Furin in promoting cell proliferation of ovarian cancer
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