Journal Article

4-HPR Is an Endoplasmic Reticulum Stress Aggravator and Sensitizes Breast Cancer Cells Resistant to TRAIL/Apo2L

NEWTON, MICHAEL A., ANDING, ALLYSON L., CLAGETT-DAME, MARGARET, CURLEY, ROBERT W., JONES, JAMES D.

2018

Overview

N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic retinoid, less toxic than the parent all-trans retinoic acid (RA). Unlike RA, 4-HPR induces apoptosis in tumor cells. Because 4-HPR can hydrolyze to liberate RA, a potent human teratogen, the unhydrolyzable ketone analog of 4-HPR, 4-hydroxybenzylretinone (4-HBR) has been prepared and has been found to cause apoptosis in tumor cells and shrink carcinogen-induced rat mammary tumors as 4-HPR does. Herein, we examined the mechanism whereby 4-HPR and 4-HBR induce apoptosis and death in breast cancer cells. Gene expression profiling was conducted in MCF-7 cells over a 1.5- to 6-h time course and changes were validated by quantitative polymerase chain reaction (qPCR). Growth arrest and DNA damage-inducible protein 153 (GADD153 or C/EBP homologous protein, CHOP) was knocked down and the effect on 4-HPR-induced cell death and gene expression was assessed. 4-HPR synergy with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL or Apo2 ligand) was also examined. Drug treatment induced increased expression of endoplasmic reticulum (ER) stress-related and pro-apoptotic genes. Gene expression changes were verified by qPCR in three invasive ductal breast carcinoma cell lines (MCF-7, T-47D, MDA-MB-231). GADD153 showed the largest increase in the microarray experiment; however, knockdown of GADD153 did not abrogate apoptosis and death. Genes related to the extrinsic pathway of apoptosis including a receptor for TRAIL, death receptor 5 (DR5), were up-regulated by drug treatment. A dose of 4-HPR that alone is ineffective in killing TRAIL-resistant MCF-7 cells, synergized with recombinant TRAIL to induce breast cancer cell death. 4-HPR and analogs might be useful in sensitizing tumor cells to death receptor agonists.

• Publisher: International Institute of Anticancer Research
• Subject: Apoptosis / Biotechnology / Breast cancer / Breast carcinoma / Carcinogens / CCAAT/enhancer-binding protein / Cell death / Cell growth / CHOP protein / Cytochrome / DNA damage / DNA microarrays / Endoplasmic reticulum / Gene expression / Genes / Ketones / Kinases / Ligands / Mortality / Polymerase chain reaction / Protein folding / Proteins / Receptors / Retinoic acid / Sensors / Signal transduction / TRAIL protein / Transcription factors / Tumor cell lines / Tumor cells / Tumor necrosis factor-TNF / Tumors / Variance analysis