BAG-1 inhibits PPARgamma-induced cell death, but not PPARgamma-induced transcription, cell cycle arrest or differentiation in breast cancer cells.
BAG-1 is a pleiotropic protein that exists as multiple isoforms. BAG-1 overexpression in breast cancer is associated with outcome. BAG-1 modulates the function of various nuclear hormone receptors, including the oestrogen receptor, and BAG-1 can influence the in vitro action of anti-hormonal therapies such as cyproterone acetate in prostate cancer. Activation of PPARgamma, a nuclear hormone receptor important for lipid and glucose homeostasis, may present a new therapeutic approach for breast cancer, since PPARgamma agonists promote cell cycle arrest, differentiation and apoptosis in breast cancer cells. Here we determined whether BAG-1 also modulated PPARgamma function in MCF7 cells. 15-deoxy-Delta12, 14-prostaglandin J(2) (15dPGJ2), an agonistic ligand for PPARgamma, induced expression of HSP70, a BAG-1 binding partner, but did not alter BAG-1 isoform expression. Overexpression of BAG-1 isoforms did not alter PPARgamma-dependent transcription or interfere with 15dPGJ2-induced cell cycle arrest or differentiation. However, overexpression of BAG-1 isoforms did interfere with induction of cell death by 15dPGJ2. Thus, BAG-1 is unlikely to directly modulate PPARgamma function, but the overexpression of BAG-1 in some breast cancers may limit the efficacy of PPARgamma agonists as cancer therapies, by suppression of PPARgamma-induced cell death pathways.
Crabb
Simon J
SJ
Cancer Research UK Clinical Centre, Cancer Sciences Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton SO16 6YD, UK.
Hague
Angela
A
Johnson
Peter W M
PW
Packham
Graham
G
D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
C097240:15-deoxy-delta(12,14)-prostaglandin J2; C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D047495:PPAR gamma; D020033:Protein Isoforms; D014157:Transcription Factors; D015230:Prostaglandin D2