Fig. 6.
Schematic diagram of proposed molecular mechanism of p27 downregulation in Fen-induced cell growth in fibroids. As reported previously, estrogen receptors (ERs) are not involved in Fen-induced cell proliferation in UtLM cells and UtSMCs (see Ref. 10). We propose that downregulation of p27 plays an essential role in Fen-induced proliferation in UtLM cells and UtSMCs. We speculate that Fen may also stimulate growth factors and their receptors, such as IGF-I and IGF-I receptor (IGF-IR), which are known regulators of uterine leiomyoma growth (see Ref. 30). Preliminary data suggest that Fen can increase the expression of Akt while downregulating the expression of forkhead box O1 (FoxO1; data not shown). Thus, Fen-induced p27 downregulation may be mediated in part by the Akt/FoxO1 signaling pathway. The downregulation of p27 leads to G1/S phase transition with accompanying increases in cyclin-dependent kinase 2 (CDK2) expression. The promotion of G1 to S phase cell cycle progression results in cell proliferation, which can contribute to tumor growth and expansion. Green shaded molecules are downregulated, whereas red shaded molecules are upregulated. Gray shaded molecule is unaffected. Akt, also known as protein kinase B, is a serine/threonine-specific protein kinase. p27, also known as p27kip1, is a CDK inhibitor.