NAMPT regulates PKM2 nuclear location through 14-3-3ζ: Conferring resistance to tamoxifen in breast cancer

The resistance against tamoxifen therapy has become one of the major obstacles in the clinical treatment of breast cancer. Nicotinamide phosphoribosyltransferase (NAMPT) is an essential enzyme catalyzing nicotinamide adenine dinucleotide biosynthesis and is important for tumor metabolism. The study here sought to explore the effect of NAMPT on breast cancer survival with tamoxifen conditioning. We found that NAMPT was highly expressed in breast cancer cells compared with normal mammary epithelial cells. Inhibition of NAMPT by FK866 inhibited cell viability and aggravated apoptosis in cancer cells treated with 4-hydroxytamoxifen. NAMPT overexpression upregulated 14-3-3 zeta expression. Knockdown of 14-3-3 zeta reduced cell survival and promoted apoptosis. Activation of Akt signaling, rather than ERK1/2 pathway, is responsible for 14-3-3 zeta regulation by NAMPT overexpression. Furthermore, NAMPT overexpression led to PKM2 accumulation in the cell nucleus and could be dampened by 14-3-3 zeta inhibition. In addition, NAMPT overexpression promoted xenografted tumor growth and apoptosis in nude mice, while 14-3-3 zeta inhibition attenuated its effect. Collectively, our data demonstrate that NAMPT contributes to tamoxifen resistance through regulation of 14-3-3 zeta expression and PKM2 translocation.