Mixed lineage kinase (MLK) family members are not involved in androgen regulation of prostatic proliferation or apoptosis.
BACKGROUND
Once paracrine growth factors are secreted by androgen receptor expressing prostatic stromal cells, they diffuse across the basement membrane of glandular acini, where they bind to epithelial cell surface receptors. This binding stimulates signaling pathways that regulate both the rate of proliferation and apoptosis of prostate epithelial cells. In the present studies, the role of mixed lineage kinases (MLKs) in these signaling processes were studied using a pharmacological approach.


METHODS
The indolocarbazole CEP-1347 (KT 7515) is a potent inhibitor of kinase activity of MKLs. Male rats were treated with CEP-1347 (1 mg/kg of body weight/day) to determine whether inhibition of the MLKs can prevent androgen ablation (i.e. castration) induced apoptosis of prostatic epithelial cells, using as indexes total ventral prostatic DNA content and the percentage of ventral prostatic epithelial cells whose DNA can be terminal transferase end-labeled. In addition, animals previously castrated a week earlier were treated daily with either vehicle or CEP-1347 and exogenous androgen replacement to induce the proliferative re-growth of the prostatic epithelial cells. After 1 week of treatment, the total ventral prostatic DNA content in the vehicle vs. CEP-1347 groups was compared.


RESULTS
Using the National Center for Bio-Informatics data bank, MLK2, MLK3, and DLK members of the MLK family are expressed by the normal prostate. Inhibition of the MLKs with CEP-1347 did not affect the kinetics of apoptosis of prostatic epithelial cells induced by androgen ablation. In addition, such MLK inhibition did not prevent androgen replacement induced proliferative regrowth of the prostate epithelium in castrated animals.


CONCLUSIONS
Signaling through the MLK family is not involved in either the androgen-induced proliferation or the androgen ablation-induced apoptosis of prostatic epithelial cell in the rat.
Gao
J
J
Johns Hopkins Oncology Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Isaacs
J T
JT
D000818:Animals; D017209:Apoptosis; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D008297:Male; D011467:Prostate / Q000166:cytology* / Q000502:physiology; D051381:Rats; D015398:Signal Transduction; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D020930:MAP Kinase Kinase Kinases; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C106592:3,9-bis((ethylthio)methyl)-K-252a; C090757:mitogen-activated protein kinase kinase kinase 12