title: Caspase-dependent cleavage of BAG3 in proteasome inhibitors-induced apoptosis in thyroid cancer cells.
abstract: 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 40kDa, which appeared to be caspase-dependent. Therefore, caspase-dependent cleavage of BAG3 might facilitate apoptosis in sensitive cells.
authors.affiliation: Department of Endocrinology and Metabolism, The 1st Affiliated Hospital, China Medical University, Shenyang 110001, China.
authors.forename: Zhen-Xian
authors.initials: ZX
authors.lastname: Du
authors.forename: Xin
authors.initials: X
authors.lastname: Meng
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Zhang
authors.forename: Yifu
authors.initials: Y
authors.lastname: Guan
authors.forename: Hua-Qin
authors.initials: HQ
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D061988:Proteasome Inhibitors; D012333:RNA, Messenger / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000201:enzymology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D020169:Caspases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde