PMID- 11850819
OWN - NLM
STAT- MEDLINE
DCOM- 20020228
LR  - 20131121
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 21
IP  - 7
DP  - 2002 Feb 7
TI  - C-Jun N-terminal kinase is required for phorbol ester- and thapsigargin-induced 
      apoptosis in the androgen responsive prostate cancer cell line LNCaP.
PG  - 1017-27
AB  - In early, androgen dependent stages of prostate cancer, androgen withdrawal, the 
      major course of therapy in prostate cancer, leads to a rapid regression of the 
      tumor as a result of apoptosis. However, prostate cancer invariably progresses to 
      an androgen independent and apoptosis resistant stage for which no curative 
      treatment is available. The molecular details of regression upon androgen 
      withdrawal and progression to a resistant state are largely unknown. Here we show 
      that c-Jun N-terminal Kinase (JNK) is activated strongly and in a sustained 
      fashion by 12-O-tetradecanoylphorbol 13-acetate (TPA) and thapsigargin (TG), two 
      agents which were previously shown to lead to apoptosis in the androgen 
      responsive prostate cancer cell line LNCaP. The time course of JNK induction by 
      both compounds correlated very well with the onset and progression of apoptosis 
      in LNCaP cells. Inhibition of either ERK or p38 pathways did not affect 
      TPA-induced cell death. In the androgen-independent prostate cancer cell lines 
      DU-145 and PC-3, and in the cervical carcinoma cell line HeLaS3, TPA did not lead 
      to apoptosis and there were no significant changes in JNK activity upon TPA 
      treatment. The failure of TPA to induce JNK activity in PC-3, DU-145, and HelaS3 
      cells was not due to a general defect in JNK signaling since ultraviolet (UV) 
      irradiation dramatically increased JNK activity in all four cell lines. Specific 
      inhibition of JNK by expression of the JNK Inhibitory Protein (JIP) dramatically 
      inhibited both TPA- and TG-induced apoptosis. Furthermore, apoptosis induced by 
      both agents was completely blocked by ectopic expression of the baculovirus 
      caspase-inhibitor P35. Surprisingly, ZVAD-fmk, a cell-permeable 
      fluoromethylketone inhibitor of caspases, had no effect on TPA-induced apoptosis, 
      whereas it completely inhibited TG-induced cell death; JNK activity was not 
      affected in either case. This indicates that ZVAD-fmk does not inhibit some of 
      the caspases involved in TPA-induced apoptosis, and that despite the common 
      requirement of JNK activation, TPA- and TG-induced cell death are mechanistically 
      different. Furthermore, it also suggests that JNK is either upstream or 
      independent of caspases in LNCaP cells. Collectively, these results indicate that 
      apoptosis in LNCaP cells requires a sustained increase in JNK activity and 
      caspase activation; components of these signaling pathways may be defective in 
      the androgen independent prostate cancer cell lines.
FAU - Engedal, Nikolai
AU  - Engedal N
AD  - Biotechnology Centre of Oslo, University of Oslo, Gaustadalleen 21, 0349 Oslo, 
      Norway.
FAU - Korkmaz, Ceren G
AU  - Korkmaz CG
FAU - Saatcioglu, Fahri
AU  - Saatcioglu F
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Androgens)
RN  - 0 (Carrier Proteins)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (MAPK8IP1 protein, human)
RN  - 0 (Viral Proteins)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - 0 (inhibitor of apoptosis, Nucleopolyhedrovirus)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - NI40JAQ945 (Tetradecanoylphorbol Acetate)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Androgens/*physiology
MH  - *Apoptosis
MH  - Carrier Proteins/genetics
MH  - Caspase Inhibitors
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Kinetics
MH  - Male
MH  - Microscopy, Fluorescence
MH  - Mitogen-Activated Protein Kinases/antagonists & inhibitors/*physiology
MH  - Prostatic Neoplasms/*enzymology/pathology
MH  - Tetradecanoylphorbol Acetate/antagonists & inhibitors/pharmacology
MH  - Thapsigargin/antagonists & inhibitors/pharmacology
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - Viral Proteins/genetics/metabolism
EDAT- 2002/02/19 10:00
MHDA- 2002/03/01 10:01
CRDT- 2002/02/19 10:00
PHST- 2001/07/03 00:00 [received]
PHST- 2001/11/02 00:00 [revised]
PHST- 2001/11/07 00:00 [accepted]
PHST- 2002/02/19 10:00 [pubmed]
PHST- 2002/03/01 10:01 [medline]
PHST- 2002/02/19 10:00 [entrez]
AID - 10.1038/sj.onc.1205167 [doi]
PST - ppublish
SO  - Oncogene. 2002 Feb 7;21(7):1017-27. doi: 10.1038/sj.onc.1205167.