Atypical induction of the unfolded protein response by mifepristone

Mifepristone is a synthetic progesterone antagonist that is being used widely for the treatment of various conditions such as endometriosis, glaucoma, meningiomas, breast, ovarian and prostate cancer, as well as for research purposes, in the conditional induction of gene expression by using artificial plasmid-based systems. Here, we report that exposure of A549 human lung cancer cells to mifepristone caused an atypical induction of the cellular unfolded protein response, as evidenced by the time-dependent stimulation of RNA levels of the chaperone Grp94 and PDIa, as well as the endoplasmic reticulum stress-associated receptors ATF6, PERK and eIF2 but not of their downstream target, transcription factor ATF4. This profile was very different from that of progesterone, which at the same dose as mifepristone, failed to induce all of the ER-stress-related genes examined, apart from PERK. Furthermore, XBP1, a transcription factor that is regulated predominantly by alternative splicing by the IRE1 receptor, remains unspliced and therefore inactive either by mifepristone or progesterone treatment. Finally, the pro-apoptotic molecules CHOP and BIM are only induced in the presence of tunicamycin in the culture medium. Tunicamycin, the most commonly used pharmacologic inducer of ER stress that triggers the canonical ER stress response, was used for comparison purposes. Our results suggest that mifepristone can elicit an atypical ER stress response when used at different doses and for different time points. The subsequent induction of UPR should be taken into consideration when this agent is being used either for therapeutic or for experimental uses.