Inhibition of c-Myc using 10058-F4 induces anti-tumor effects in ovarian cancer cells via regulation of FOXO target genes

Abstract

Ovarian cancer, characterized by rapid growth and asymptomatic development in the early stage, is the fifth common cancer in women. The deregulated expression of c-Myc in more than 50% of human tumors including ovarian cancer makes this oncogenic master transcription factor a potential therapeutic target for cancer treatment. In the present study, we evaluated the anti-tumor effects of 10058-F4, a small molecule c-Myc inhibitor, on ovarian cancer cells. We found that 10058-F4 not only inhibited the proliferation and clonal growth of ovarian cancer cells but also enhanced the cytotoxic effects of chemotherapeutic drugs. Our results also revealed that c-Myc inhibition using 10058-F4 increased the intracellular reactive oxygen species production coupled with suppressed expression of hTERT. RT-qPCR analysis indicated that 10058-F4 enhanced the mRNA levels of the forkhead box O (FOXO) family of transcription factors, including FOXO1, 3, and 4. Moreover, 10058-F4 induced G1 cell cycle arrest in 2008C13 ovarian cancer cells, along with increased expression of some key targets of FOXOs involved in the regulation of cell cycle such as p15, p21, p27, and GADD45A. The results of our study also showed that the 10058-F4-induced apoptosis in 2008C13 cell line was associated with the upregulation of FOXO downstream genes, including PUMA, Bim, and FasL. In conclusion, our results, for the first time, suggest that the anti-tumor effects of 10058-F4 in ovarian cancer cells might be mediated through upregulation of FOXO transcription factors and their key target genes involved in G1 cell cycle arrest, apoptosis, and autophagic cell death.