Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis.
Recent studies have suggested that MAP kinase phosphatase 1 (MKP-1) is overexpressed in prostate cancer. To evaluate the role of MKP-1 in regulating cell death and tumor growth in prostate cancer, MKP-1 was conditionally overexpressed in the human prostate cancer cell line DU145. Overexpression of MKP-1 in DU145 cells blocked activation of stress-activated protein kinase (SAPK/JNK). MKP-1 overexpression in DU-145 cells was also found to inhibit Fas ligand (FasL)-induced apoptosis, as well as block the activation of caspases by Fas engagement. In addition, MKP-1 blocked the activation of apoptosis by transfected MEKK-1 and ASK-1, presumably through its inhibition of the SAPK/JNK family of enzymes. MKP-1 blocked the ability of FasL to induce loss of mitochondrial transmembrane potential (delta Psi(m)), suggesting that MKP-1 acts upstream of mitochondrial pro-apoptotic events induced by FasL and that the SAPK/JNK pathway may form the signaling link between Fas receptor and mitochondrial dysfunction. Thus, MKP-1 overexpression in prostate cancer may play a role in promoting prostate carcinogenesis by inhibiting FasL-induced cell death.
Srikanth
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S
Division of Medical Oncology, University of Colorado, Health Sciences Center, Denver, USA.
Franklin
C C
CC
Duke
R C
RC
Kraft
R S
RS
D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008564:Membrane Potentials; D008668:Metallothionein / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism*; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D008668:Metallothionein; D048057:Mitogen-Activated Protein Kinase 10; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482576:MAP3K1 protein, human; C482858:MAP3K5 protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D020169:Caspases