Acacetin induces sustained ERK1/2 activation and RIP1-dependent necroptotic death in breast cancer cells

Acacetin (AC), a naturally occurring flavonoid has shown anticancer potential. Herein, we studied the mecha-nisms of cell death and growth inhibition by AC in breast carcinoma T-47D and MDA-MB-231 cells. AC (10-40 mu M) significantly decreased the levels of G2/M phase cyclins and CDKs, simultaneously increasing the expression of CDK inhibitors including Cip1/p21. A concentration-dependent increase in cell death was noted in both breast cancer cell lines with no such considerable effects on MCF-10A non-tumorigenic breast cells. The cell death -inducing potential of AC was further confirmed using confocal microscopy and flow cytometry analysis. AC resulted in mitochondrial superoxide generation, DNA damage, and ROS generation. N-acetyl cysteine (NAC) pre-treatment inhibited ROS generation and partially reversed ERK1/2 activation as well as cell death by AC. Further, AC enhanced the expression of RIP1 and RIP3, which mediate necroptosis. RIP1-specific inhibitor Necrostatin-1 (NS-1) reversed the AC-induced DNA damage and cell death. Collectively, these findings, for the first time, suggested that AC exerts its antitumor potential through ROS induction and RIP1-dependent nec-roptosis in breast carcinoma cells.

Automated summary

Acacetin (AC), a naturally occurring flavonoid, has been found to have anticancer potential. This study revealed that AC inhibits cell proliferation and induces cell death in breast carcinoma cells through regulating cell cycle and CDKs levels, as well as inducing ROS generation and RIP1-dependent necroptosis.