Targeting FASN in Breast Cancer and the Discovery of Promising Inhibitors from Natural Products Derived from Traditional Chinese Medicine

Figure 3

FASN inhibition and cancer cell death related pathways. Inhibiting FASN by either drug or by gene silencing can inhibit HER2 expression; meanwhile, HER2 overexpression leads to an increased expression of FASN, indicating that there is a bidirectional regulation mechanism between FASN and HER2. FASN expression can be not only regulated by SPEBT-1c but also controlled by other transcription factors, such as p53 family proteins and the lipogenesis-related nuclear protein, SPOT14, which is overexpressed in breast cancer. The steroid hormones binding with steroid hormone receptors can also activate similar pathways. These two pathways stimulate FASN expression by the gene modulation and/or the nuclear maturation of the sterol regulatory element-binding protein 1c (SREBP1C), which is a transcription factor that activates FASN by binding to its promoter region, which contains sterol regulatory elements [32]. Currently, there are several pathways that contribute to the initiation of FASN cytotoxicity. One is where FASN inhibition initiates a more effective apoptosis in cells with nonfunctioning p53 protein compared to those cells with functioning p53 protein, which occurs concurrently with cytostatic response. One is where HER2 overexpressed cells are also linked to FASN induced cytotoxicity. In addition, there are studies on ovarian cancer cell lines showing that FASN activity modulates Akt activation, and, at the same time, Akt activation regulates FASN expression, suggesting that the Akt activation protects cells against FASN inhibitor induced cell death.