Proteasome inhibitors induce a p38 mitogen-activated protein kinase (MAPK)-dependent anti-apoptotic program involving MAPK phosphatase-1 and Akt in models of breast cancer.
Proteasome inhibitors represent a novel class of anti-tumor agents that have clinical efficacy against hematologic malignancies, but single-agent activity against solid tumors such as breast cancer has been disappointing, perhaps due to activation of anti-apoptotic survival signals. To evaluate a possible role for the p38 mitogen-activated protein kinase (MAPK), A1N4-myc human mammary epithelial, and BT-474 and MDA-MB-231 breast carcinoma cells, were studied. Exposure of these lines to pharmacologic p38 blockade enhanced proteasome inhibitor-mediated apoptosis, as did overexpression of dominant negative (DN)-p38-alpha and -beta-MAPK isoforms. Inhibition of p38 resulted in suppression of induction of anti-apoptotic MAPK phosphatase (MKP)-1, in association with enhanced activation of the pro-apoptotic c-Jun-N-terminal kinase (JNK). Moreover, infection of cells treated with a proteasome inhibitor/p38 inhibitor combination with Adenovirus (Ad) inducing over-expression of MKP-1 suppressed apoptosis compared with controls. Further targets of p38 MAPK were also studied, and proteasome inhibition activated phosphorylation of MAPK-activated protein kinase-2, heat shock protein (HSP)-27, and the AKT8 virus oncogene cellular homolog (Akt). Inhibition of p38 MAPK resulted in decreased phospho-HSP-27 and phospho-Akt, while down-regulation of HSP-27 with a small interfering RNA decreased phosphorylation of Akt, directly linking activation of p38 to Akt. Finally, inhibition of Akt with phosphatidylinositol-3-kinase inhibitors increased apoptosis, as did over-expression of DN-Akt. These studies support the hypothesis that proteasome inhibitors activate an anti-apoptotic survival program through p38 MAPK that involves MKP-1 and Akt. Further, they suggest that strategies targeting MKP-1 and Akt could enhance the anti-tumor efficacy of proteasome inhibitors against breast cancer.
Shi
Yue Y
YY
22-003 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, CB # 7295, Mason Farm Road, Chapel Hill, NC 27599-7295, USA.
Small
George W
GW
Orlowski
Robert Z
RZ
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D054638:Dual Specificity Phosphatase 1; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism
D001897:Boronic Acids; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases