Aluminum chloride induces G0/G1 phase arrest via regulating the reactive oxygen species-depended non-canonical STAT1 pathway in hFOB1.19 cells

Abstract

Treatment with aluminum chloride (AlCl3) suppresses the growth of osteoblastic cells; however, the molecular mechanisms underlying the impact of AlCl3 on cell growth have not been fully characterized. In this study, we observed that exposure of hFOB1.19 cells to AlCl3 arrested cells at G0/G1 phase by inducing p21 expression. Further studies indicated that AlCl3 upregulated the phosphorylation level of signal transducer and activator of transcription 1 (STAT1) at serine 727 site (Ser727). By chromatin immunoprecipitation and electrophoretic mobility shift assay, we found that AlCl3 promoted STAT1/DNA binding activity to p21 promoter, thus resulting in the upregulation of p21. Moreover, siRNA-mediated knockdown of STAT1 attenuated p21 level induced by AlCl3. Notably, using hFOB1.19 cells stably expressing dominant-negative STAT1 (Ser727Ala), we demonstrated that phosphorylation of STAT1 at Ser727 site is required for p21-mediated cycle arrest induced by AlCl3. Mechanism investigation indicated that AlCl3 stimulated the phosphorylation of JNK, and administration of JNK inhibitor SP600125 prevented AlCl3-induced G0/G1 arrest through suppressing the phosphorylation of STAT1. Notably, pretreatment with N-acetyl-cysteine, a reactive oxygen species scavenger, conferred a significantly inhibitory effect on AlCl3-mediated activation of JNK/STAT1 signaling pathway. Taken together, our findings provide the molecular mechanism for G0/G1 arrest induced by AlCl3 in osteoblastic cells.

STAT1 negatively regulates human glioma U251 cell proliferation Huang et al: Role of STAT1 in glioma

“…The results implied that the change of p21 modulated by the STAT1 gene might influence the cell cycle distribution caused by AlCl 3 . 28,32 B-cell lymphoma-2 (bcl-2) family proteins are essential modulators of programmed cell death and apoptosis and play a prominent role in human cancer. Bcl-2 protein can regulate the appropriate Ca 2 + concentration in the endoplasmic reticulum and mitochondria, keep them in dynamic balance, and avoid cell apoptosis caused by excessive Ca 2 + concentration in mitochondria.…”