Proteasome inhibitors are emerging as effective drugs for the treatment of relapsed/refractory multiple myeloma and possibly some solid tumors. Bcl-2-associated athanogene 3 (BAG3) is a survival protein that has been shown to be stimulated during cell response to stressful conditions, such as exposure to high temperature, heavy metals. We have recently demonstrated that BAG3 is also induced by proteasome inhibitors at the transcriptional level and the induction of BAG3 by proteasome inhibition is antiapoptotic. Here, we demonstrated that although proteasome inhibitors triggered similar upregulation of BAG3 transcript in sensitive and insensitive thyroid cancer cells, persistent increase of BAG3 protein was detected in insensitive cells, whereas less increase or even decrease was observed in sensitive cells. Notably, decrease of BAG3 protein was associated with the appearance of a BAG3 fragment of approximately 40 kDa, which appeared to be caspase-dependent. Therefore, caspase-dependent cleavage of BAG3 might facilitate apoptosis in sensitive cells. (c) 2008 Elsevier Inc. All rights reserved.