FASN inhibition shows the potential for enhancing radiotherapy outcomes by targeting glycolysis, AKT, and ERK pathways in breast cancer

Purpose: Breast cancer ranks as the most prevalent cancer in women, characterized by heightened fatty acid synthesis and glycolytic activity. Fatty acid synthase (FASN) is prominently expressed in breast cancer cells, regulating fatty acid synthesis, thereby enhancing tumor growth and migration, and leading to radioresistance. This study aims to investigate how FASN inhibition affects cell proliferation, migration, and radioresistance in breast cancer, as well as the mechanisms involved.

Materials and methods: We used lentiviruses carrying shFASN to create FASN-knockdown cell lines called MCF-7-shFASN and MDA-MB-231-shFASN. We conducted Western blot analysis to determine the expression levels of FASN and other proteins of interest. Furthermore, we evaluated cellular glucose uptake and migration using the ¹⁸F-FDG assay, wound healing, and transwell assays. We also employed the MTT assay to assess the short-term survival of the negative control and FASN-knockdown cells after irradiation.

Results: FASN knockdown led to a decrease in the expressions of proteins related to fatty acid synthesis and glycolysis in both MCF-7-shFASN and MDA-MB-231-shFASN cells when compared to their counterparts. Moreover, reduced ¹⁸F-FDG uptake and lactate production were also detected after FASN knockdown. FASN knockdown inhibited cell proliferation and survival by downregulating the AKT, ERK, and AMPK pathways and promoted apoptosis by increasing the BAX/p-Bcl-2 ratio. In addition, FASN knockdown impaired cell migration while enhancing radiosensitivity.

Conclusions: FASN knockdown disrupts fatty acid synthesis and glycolysis, inhibits cell proliferation and induces apoptosis. The increased radiosensitivity after FASN inhibition suggests that it could potentially complement radiotherapy in treating breast cancer.