The Retinoid Antagonist MX781 Induces Clusterin Expression in Prostate Cancer Cells via Heat Shock Factor-1 and Activator Protein-1 Transcription Factors

Abstract

Retinoids mediate numerous biological responses through the transcriptional activation of nuclear retinoid receptors. Due to their antiproliferative activity, retinoids have shown promise as anticancer agents. Synthetic analogs have been described that selectively activate one subset of the retinoid receptors or inhibit their transcriptional activity. Some of these compounds exhibit strong anticancer activity, which is associated with their ability to induce apoptosis. Here we describe that the retinoid antagonist MX781 causes a substantial increase of clusterin mRNA and protein levels in prostate carcinoma cells. In contrast, retinoic acid and other synthetic agonists and antagonists show no effect on clusterin mRNA/protein levels. Induction of clusterin mRNA is associated with transcriptional activation of the clusterin promoter, which requires the proximal ؊218-bp region containing binding sites for heat shock factor (HSF)-1, activator protein (AP)-2, and AP-1 transcription factors. MX781 slightly induces AP-1 DNA binding activity, and mutation of the AP-1 site differentially affects the activation of the clusterin promoter in a cell type-specific manner. In contrast, a robust increase of HSF-1 DNA binding activity is observed in all cancer cell lines examined, and mutation of the heat shock element site in the clusterin promoter completely abolishes MX781-induced transcriptional activation in PC3 and DU145 cells. Other agonist retinoid-related molecules also induce AP-1 activity, but not HSF-1, and elicit no effect on clusterin expression levels. These data point to HSF-1 as an important factor regulating clusterin expression in response to MX781, although AP-1 activity may also participate in a cell type-specific manner.

Clusterin Mediates TGF-β–Induced Epithelial–Mesenchymal Transition and Metastasis via Twist1 in Prostate Cancer Cells

“…For example, heat shock factor-1 (HSF-1) is a well-known regulator of CLU expression by binding CLE sites in CLU promoter regions (39). In addition, AP-1 and Egr-1 also regulate CLU expression (13,40). Furthermore, we recently reported that Y-box binding protein-1 is a key transcriptional factor that induces CLU expression during endoplasmic reticulum stress (15).…”

Delayed Activation of Insulin-like Growth Factor-1 Receptor/Src/MAPK/Egr-1 Signaling Regulates Clusterin Expression, a Pro-survival Factor

“…sCLU was induced by Ն2 cGy in various breast and colon cancer cells, with peak induction of sCLU noted 24 -72 h after IR, as measured by promoter activity, transcript, and protein levels (7). Although specific transcription factors have been implicated in sCLU regulation after specific genotoxic stresses, including repression by c-Fos (25) and possible activation by c-Myc (19) and AP-1 (26), the signaling pathways involved and transcription factors that directly regulate the expression of this gene after IR have not been elucidated.…”

Clusterin Facilitates COMMD1 and I-κB Degradation to Enhance NF-κB Activity in Prostate Cancer Cells

“…sCLU interacts with and inhibits conformationally-altered Bax in response to cytotoxic stress thereby impeding Bax oligomerization, cytochrome C release, and intrinsic pathway activation (2). sCLU is transcriptionally activated by heath shock factor (HSF-1) (3, 4) and increased levels are associated with a broad range of normal and disease states including aggregopathies in Alzheimer’s Disease (5), mammary gland involution (6) and treatment resistance in cancer. In cancer, sCLU is highly expressed in cells surviving apoptotic stimuli and in advanced and treatment resistant cancers (7), and protects cells against apoptosis in response to hormone-, radiation-, and chemo-therapy (7–9).…”