Differentiation‐inducing factor‐1 suppresses cyclin D1‐induced cell proliferation of MCF‐7 breast cancer cells by inhibiting S6K‐mediated signal transducer and activator of transcription 3 synthesis. Issue 12 (26th October 2019)

• Record Type: Journal Article
• Authors: Tetsuo, Fumi; Arioka, Masaki; Miura, Koichi; Kai, Misato; Kubo, Momoko; Igawa, Kazunobu; Tomooka, Katsuhiko; Takahashi‐Yanaga, Fumi; Nishimura, Fusanori; Sasaguri, Toshiyuki
• Is Part Of: Cancer science. Volume 110:Issue 12(2019)
• Page Start: 3761
• Page End: 3772
• Publication Date: 2019-10-26
• Subjects: cyclin D1 -- differentiation‐inducing factor‐1 -- protein synthesis -- ribosomal protein S6 kinase -- signal transducer and activator of transcription 3; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14204
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Differentiation‐inducing factor‐1 (DIF‐1) has been reported to inhibit the proliferation of various mammalian cells by unknown means, although some possible mechanisms of its action have been proposed, including the activation of glycogen synthase kinase‐3 (GSK‐3). Here, we report an alternative mechanism underlying the action of DIF‐1 in human breast cancer cell line MCF‐7, on which the effects of DIF‐1 have not been examined previously. Intragastric administration of DIF‐1 reduced the tumor growth from MCF‐7 cells injected into a mammary fat pad of nude mice, without causing adverse effects. In cultured MCF‐7, DIF‐1 arrested the cell cycle in G0 /G1 phase and suppressed cyclin D1 expression, consistent with our previous results obtained in other cell species. However, DIF‐1 did not inhibit the phosphorylation of GSK‐3. Investigating an alternative mechanism for the reduction of cyclin D1, we found that DIF‐1 reduced the protein levels of signal transducer and activator of transcription 3 (STAT3). The STAT3 inhibitor S3I‐201 suppressed cyclin D1 expression and cell proliferation and the overexpression of STAT3 enhanced cyclin D1 expression and accelerated proliferation. Differentiation‐inducing factor‐1 did not reduce STAT3 mRNA or reduce STAT3 protein in the presence of cycloheximide, suggesting that DIF‐1 inhibited STAT3 protein synthesis. Seeking its mechanism, we revealed that DIF‐1 inhibited the activation of 70 kDa and/or 85 kDa ribosomal protein S6 kinase (p70 S6K /p85 S6K ). Inhibition of p70 S6K /p85 S6K by rapamycin also reduced the expressions of STAT3 and cyclin D1. Therefore, DIF‐1 suppresses MCF‐7 proliferation by inhibiting p70 S6K /p85 S6K activity and STAT3 protein synthesis followed by reduction of cyclin D1 expression. Abstract : In the present study, we showed that differentiation‐inducing factor‐1 inhibits the growth of MCF‐7‐derived tumors in vivo and the proliferation of cultured MCF‐7 cells in vitro, in agreement with our previous studies on the differentiation‐inducing factors' action. By contrast, the underlying mechanism here is different from that in the cells examined previously. In MCF‐7, DIF‐1 appeared to suppress cyclin D1 expression in two ways: (i) acceleration of this protein's degradation by an unidentified, glycogen synthase kinase‐3‐independent mechanism; and (ii) inhibition of cyclin D1 gene expression by downregulation of signal transducer and activator of transcription 3 (STAT3), the mechanisms for which could involve the inhibition of STAT3 mRNA translation to the protein by the reduction of phosphorylated p70S6K/p85S6K.