HSF1-mediated BAG3 expression attenuates apoptosis in 4-hydroxynonenal-treated colon cancer cells via stabilization of anti-apoptotic Bcl-2 proteins.

Abstract

4-Hydroxynonenal (HNE) is a pro-apoptotic electrophile generated during the spontaneous decomposition of oxidized lipids. We have previously shown that HNE activates the transcription factor, heat shock factor 1 (HSF1), and promotes cytoprotective heat shock gene expression and that silencing HSF1 sensitizes the colon cancer cell line RKO to HNE-induced apoptosis. Here we report a reduction in the anti-apoptotic proteins Bcl-X(L), Mcl-1, and Bcl-2 in HSF1-silenced RKO cells, and we examine the underlying mechanism. To investigate the regulation of the Bcl-2 family by HSF1, microarray analysis of gene expression was performed. We observed that the Hsp70 co-chaperone, BAG3 (Bcl-2-associated athanogene domain 3), is strongly induced by HNE in control but not in HSF1-silenced colon cancer cells. Silencing BAG3 expression with small interfering RNA caused a dramatic reduction in Bcl-X(L), Mcl-1, and Bcl-2 protein levels in colon cancer cells and increased apoptosis, similar to the effect of silencing HSF1. Also, immunoprecipitation experiments indicate specific interactions between BAG3, Hsp70, and the Bcl-2 family member, Bcl-X(L). Overall, our data reveal that BAG3 is HSF1-inducible and has a unique role facilitating cancer cell survival during pro-apoptotic stress by stabilizing the level of Bcl-2 family proteins.

• Authors: Aaron T Jacobs, Lawrence J Marnett
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 14 Pg. 9176-83 (Apr 03 2009) ISSN: 0021-9258 [Print] United States
• PMID: 19179333 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Aldehydes
• DNA-Binding Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Transcription Factors
• 4-hydroxy-2-nonenal

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Aldehydes (pharmacology)
• Apoptosis (drug effects)
• Cell Line
• DNA-Binding Proteins (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Myeloid Cell Leukemia Sequence 1 Protein
• Oligonucleotide Array Sequence Analysis
• Protein Binding
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Transcription Factors (genetics, metabolism)