Abstract
Oxygen-regulated protein 150 (ORP150) is an inducible ER chaperone by numerous cellular insults and sustains cellular viability. We have previously reported that ORP150 is differentially induced in a panel thyroid cancer cells and represents as an unwanted molecular consequence during exposure to proteasome inhibition. However, the molecular basis for induction of ORP150 by proteasome inhibitors in thyroid cancer cells remains unclear. In the current study, we found that −421/−307 and −243/+53 regions at the ORP150 gene were responsible for its transactivation by MG132 in thyroid cancer cells. Nrf2 directly transactivated the ORP150 gene by direct binding with the −421/−307 region. Nrf2 also indirectly activated OPR150 transcription via facilitating recruitment of ATF4 to the −243/+53 region. Collectively, this study highlights the molecular mechanism by which proteasome inhibition stimulates ORP150 expression via Nrf2 in thyroid cancer cells.
Highlights
Proteasome inhibitors possess anti-tumor activity against hematologic malignancies and solid tumors [1]
To examine whether transactivation of the Oxygen-regulated protein 150 (ORP150) gene might lead to its induction by MG132 in thyroid cancer 8305C cells, we used a reporter construct containing -1079 to +53 base pairs of the human ORP150 promoter fused to luciferase (pORP150(1079/+53)-Luc). 8305C cells were chosen for the current study, because they demonstrated the highest ORP150 induction by MG132 in a panel of thyroid cancer cell lines [8]
ORP150 is an inducible endoplasmic reticulum (ER) chaperone molecule that is increased by various stimuli including hypoxia, serum starvation, ischemia, ER stressors and proteasome inhibitors [2, 4, 8, 12,13,14, 18, 21, 25]
Summary
Proteasome inhibitors possess anti-tumor activity against hematologic malignancies and solid tumors [1]. Proteasome inhibition may lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen resulting in ER stress response, a process involving three ER transmembrane proteins: protein-kinase and site-specific endoribonuclease (IRE1), protein kinase R-like ER kinase (PERK), and activating transcription factor (ATF) 6 [5]. ER stressors induce phosphorylation of PERK and IRE1, which in turn lead to ATF4 activation and XBP1 splicing, respectively [16]. ER stressors trigger cleavage of p90-ATF6 into p50-ATF6, which translocates to the nucleus and activates the target genes [32]. All ATF4, XBP1 and p50-ATF6 activate transcription of ER stress response-related genes containing ER stress response element (ERSE) [17]. Accumulating studies support that ER stress is implicated in the antitumor effects of proteasome inhibitors [7, 19, 23, 24, 30]
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