Acyl-CoA synthetase-4 mediates radioresistance of breast cancer cells by regulating FOXM1

Abstract

The development of radioresistance during radiotherapy is a major cause of tumor recurrence and metastasis. To provide new insights of the mechanisms underlying radioresistance, we established radioresistant cell lines derived from two different subtypes of breast cancer cells, HER2-positive SK-BR-3 and ER-positive MCF-7 breast cancer cells, by exposing cells to 48 ~ 70 Gy of radiation delivered at 4-5 Gy twice weekly over 9 ~ 10 months. The established radioresistant SK-BR-3 (SR) and MCF-7 (MR) cells were resistant not only to a single dose of radiation (2 Gy or 4 Gy) but also to fractionated radiation delivered at 2 Gy/day for 5 days. Furthermore, these cells exhibited tumor-initiating potential in vivo and high CD24-/CD44 + ratio. To identify novel therapeutic molecular targets, we analyzed differentially expressed genes in both radioresistant cell lines and found that the expression of ACSL4 was significantly elevated in both cell lines. Targeting ACSL4 improved response to irradiation and inhibited migration activities. Furthermore, inhibition of ACLS4 using ASCL4 siRNA or triacsin C suppressed FOXM1 expression, whereas inhibition of FOXM1 using thiostrepton did not affect ACSL4 expression. Targeting the ACSL4-FOXM1 signaling axis by inhibiting ASCL4 or FOXM1 overcame the radioresistance by suppressing DNA damage responses and inducing apoptosis. This is the first study to report that ACSL4 plays a crucial role in mediating the radioresistance of breast cancer by regulating FOXM1. We propose the ACSL4-FOXM1 signaling axis be considered a novel therapeutic target in radioresistant breast cancer and suggest treatment strategies targeting this signaling axis might overcome breast cancer radioresistance.

Keywords: ACSL4; Breast cancer; FOXM1; Radioresistance; Radiotherapy.