SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via induction of NAD+ depletion-dependent activation of ATF3
Xi chen,
Zhenchuan Wang,
Chen Li,
Zhao Zhang,
Shan Lu,
Xuanzhong Wang,
Qi Liang,
Xiaoxi Zhu,
Chengliang Pan,
Qingxuan Wang,
Zhilin Ji,
Yubo Wang,
Meihua Piao,
Guangfan Chi,
Pengfei Ge
Affiliations
Xi chen
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
Zhenchuan Wang
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
Chen Li
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
Zhao Zhang
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China
Shan Lu
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
Xuanzhong Wang
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
Qi Liang
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
Xiaoxi Zhu
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
Chengliang Pan
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
Qingxuan Wang
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
Zhilin Ji
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
Yubo Wang
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China
Meihua Piao
Department of Anesthesiology, First Hospital of Jilin University, Changchun, 130021, China
Guangfan Chi
Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China
Pengfei Ge
Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China; Research Center of Neuroscience, First Hospital of Jilin University, Changchun, 130021, China; Corresponding author. Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, China.
Ferroptosis is a type of programmed cell death resulting from iron overload-dependent lipid peroxidation, and could be promoted by activating transcription factor 3 (ATF3). SIRT1 is an enzyme accounting for removing acetylated lysine residues from target proteins by consuming NAD+, but its role remains elusive in ferroptosis and activating ATF3. In this study, we found SIRT1 was activated during the process of RSL3-induced glioma cell ferroptosis. Moreover, the glioma cell death was aggravated by SIRT1 activator SRT2183, but suppressed by SIRT inhibitor EX527 or when SIRT1 was silenced with siRNA. These indicated SIRT1 sensitized glioma cells to ferroptosis. Furthermore, we found SIRT1 promoted RSL3-induced expressional upregulation and nuclear translocation of ATF3. Silence of ATF3 with siRNA attenuated RSL3-induced increases of ferrous iron and lipid peroxidation, downregulation of SLC7A11 and GPX4 and depletion of cysteine and GSH. Thus, SIRT1 promoted glioma cell ferroptosis by inducting ATF3 activation. Mechanistically, ATF3 activation was reinforced when RSL3-induced decline of NAD+ was aggravated by FK866 that could inhibit NAD + synthesis via salvage pathway, but suppressed when intracellular NAD+ was maintained at higher level by supplement of exogenous NAD+. Notably, the NAD + decline caused by RSL3 was enhanced when SIRT1 was further activated by SRT2183, but attenuated when SIRT1 activation was inhibited by EX527. These indicated SIRT1 promoted ATF3 activation via consumption of NAD+. Finally, we found RSL3 activated SIRT1 by inducing reactive oxygen species-dependent upregulation of AROS. Together, our study revealed SIRT1 activated by AROS sensitizes glioma cells to ferroptosis via activation of ATF3-dependent inhibition of SLC7A11 and GPX4.
