Pro-apoptotic tumor necrosis factor-alpha transduction pathway in normal prostate, benign prostatic hyperplasia and prostatic carcinoma.
OBJECTIVE
Tumor necrosis factor-alpha (TNF-alpha) exerts apoptosis throughout an intracellular transduction pathway that involves the protein kinases TRAF-2 (integration point of apoptotic and survival signals), signal regulating kinase (ASK-1) (pro-apoptotic protein), mitogen activated protein kinase-kinase 4 (MEK-4) (p38 activator and metastasis suppressor gene), Jun N-terminal kinase (JNK) (stress mitogen activated protein kinase) and the transcription factor activator protein-1 (AP-1).


METHODS
Biopsies from 20 normal, 35 hyperplastic and 27 carcinomatous human prostates were obtained for immunohistochemical and Western blot studies of the mentioned TNF-alpha/AP-1 transduction pathway members.


RESULTS
In normal prostates immunoreactions to TRAF-2, ASK-1, MEK-4 and JNK were positive, while no immunoreaction to AP-1 was detected. Although in benign prostatic hyperplasia the percent of immunostained specimens and intensity of immunoreactions to TRAF-2, ASK-1, MEK-4 and JNK decreased, the immunoreaction to AP-1 was positive in 27.3%. In most carcinomatous specimens the immune reaction was negative for all proteins of the TRAF-2/AP-1 pathway.


CONCLUSIONS
The TNF-alpha/AP-1 pathway might be a response to the excessive proliferative stimulus, although this response seems to be insufficient to counteract extracellular signals of cell proliferation. In prostate cancer this pathway is probably inactivated by other factors, such as p21 (at the ASK-1 level) or bcl-2 (at the JNK level).
Ricote
Monica
M
Department of Cell Biology and Genetics, University of Alcalá, E-28871 Alcalá de Henares, Madrid, Spain.
Royuela
Mar
M
García-Tuñón
Ignacio
I
Bethencourt
Fermín R
FR
Paniagua
Ricardo
R
Fraile
Benito
B
D000199:Actins / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011467:Prostate / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000199:Actins; D018797:Cell Cycle Proteins; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048768:MAP Kinase Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; C482779:MAP3K4 protein, human; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases