TY - JOUR
T1 - Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis
AU - Srikanth, Sampathkumar
AU - Franklin, Christopher C.
AU - Duke, Richard C.
AU - Kraft, Andrew S.
N1 - Funding Information:
The authors wish to thank Dr. J. Lipsick for the bipartite LacZ vector, Dr. D. Templeton for the ∆MEKK-1 expression plasmid, Dr. H. Ichijo for the ASK1 plasmid, Dr. N. Tonks for the MKP-1 cDNA, and Dr. P. Keiner for the sFasL supernatants. We also wish to thank Drs. Cohen and Lamb for help with caspase assays. Members of the Kraft laboratory were most helpful with their suggestions. This work was supported by CA78631(ASK), AI40394, AI40607, and the Immunology Core of the University of Colorado Cancer Center CA46934 (RCD), the UCCC Wines for Life seed grant (SS), and ACS-IRG 5-37 (CCF).
PY - 1999
Y1 - 1999
N2 - 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 (ΔΨ(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.
AB - 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 (ΔΨ(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.
KW - Apoptosis
KW - Fas
KW - Fas ligand
KW - MKP-1
KW - Prostate cancer
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U2 - 10.1023/A:1006980326855
DO - 10.1023/A:1006980326855
M3 - Article
C2 - 10544965
AN - SCOPUS:0032877013
SN - 0300-8177
VL - 199
SP - 169
EP - 178
JO - Molecular and Cellular Biochemistry
JF - Molecular and Cellular Biochemistry
IS - 1-2
ER -