Abstract
Excessive and persistent insults during endoplasmic reticulum (ER) stress lead to apoptotic cell death that is implicated in a range of chronic inflammatory diseases and cancers. Macrophage inhibitory cytokine 1 (MIC-1), a member of the transforming growth factor-β superfamily, is diversely linked to the pathogenesis of cancer. To investigate the precise molecular mechanisms of MIC-1 gene regulation, ER stress and its related signals were studied in human colon cancer cells. Functionally, MIC-1 played pivotal roles in ER stress-linked apoptotic death, which was also influenced by C/EBP homologous protein, a well known apoptotic mediator of ER stress. ER stress enhanced MIC-1 mRNA stability instead of transcriptional activation, and there were two mechanistic translocations critical for mRNA stabilization. First, C/EBP homologous protein triggered protein kinase C-linked cytosolic translocation of the HuR/ELAVL1 (Elav-like RNA-binding protein 1) RNA-binding protein, which bound to and stabilized MIC-1 transcript. As the second critical in-and-out regulation, ER stress-activated ERK1/2 signals contributed to enhanced stabilization of MIC-1 transcript by controlling the extended holding of the nucleated mRNA in the stress granules fusing with the mRNA-decaying processing body. We propose that these two sequential in-and-out modulations can account for stabilized transcription and subsequent translation of pro-apoptotic MIC-1 gene in human cancer cells under ER stress.
Highlights
Modulation of a pro-apoptotic Macrophage inhibitory cytokine 1 (MIC-1) was addressed under endoplasmic reticulum (ER) stress-linked alterations of intracellular components
ER Stress-induced MIC-1 Is Linked with Cancer Cell Apoptosis—In the present study, MIC-1 was assessed as a proapoptotic mediator in response to ER stress that was induced by representative chemical triggers, including thapsigargin (TG) and tunicamycin, in human intestinal cancer cells
MIC-1 induction by ER stress was observed in other epithelial cancer cells, such as HCT-8 and HT-29 cells (Fig. 1, B and C), and the chemical-induced ER stress increased MIC-1 gene expression in a dose-dependent manner (Fig. 1D)
Summary
Modulation of a pro-apoptotic MIC-1 was addressed under ER stress-linked alterations of intracellular components. ER stress enhanced MIC-1 mRNA stability instead of transcriptional activation, and there were two mechanistic translocations critical for mRNA stabilization. As the second critical in-and-out regulation, ER stress-activated ERK1/2 signals contributed to enhanced stabilization of MIC-1 transcript by controlling the extended holding of the nucleated mRNA in the stress granules fusing with the mRNA-decaying processing body. We propose that these two sequential in-andout modulations can account for stabilized transcription and subsequent translation of pro-apoptotic MIC-1 gene in human cancer cells under ER stress
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