Tyrosine kinase inhibitors reduce bcl-2 expression and induce apoptosis in androgen-dependent cells.
The signal transduction pathway showing how androgen withdrawal induces apoptosis in androgen-dependent cells has not been clearly understood. In these studies, we focused on the behavior of tyrosine kinases in androgen-dependent cells and investigated its correlation with apoptosis and bcl-2 expression. We used SC2G, an androgen-dependent mouse mammary carcinoma cell line, which had been cloned from Shionogi Carcinoma 115 (SC115). When SC2G cells were cultured with herbimycin A (HMA), a potent tyrosine kinase inhibitor, the number of viable cells decreased significantly after 24 h. Terminal deoxyribonucleotidyltransferase-mediated dUTP-biotin nick end labeling and flow cytometric analysis of annexin V staining showed that HMA induced apoptosis of SC2G cells. The level of bcl-2 mRNA in SC2G cells was suppressed by HMA in a dose-dependent manner on RT-PCR. Preincubation with caspase inhibitors protected HMA-induced apoptosis of SC2G cells. When a human bcl-2 gene was transfected in SC2G cells and overexpressed, SC2G cells seemed to acquire tolerance for HMA. These data indicate that HMA-sensitive tyrosine kinase(s) can regulate apoptosis and inhibit bcl-2 expression in SC2G mouse androgen-dependent cells. Tyrosine kinase(s) seemed to be a member of signal transduction between androgen receptor activation and bcl-2 expression.
Ohigashi
T
T
Department of Urology, Kidney Center, Saitama Medical School, Moroyamamachi 350-0495, Japan. ohigashi@med.keio.ac.jp
Ueno
M
M
Nonaka
S
S
Nakanoma
T
T
Furukawa
Y
Y
Deguchi
N
N
Murai
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones; D020169:Caspases / Q000378:metabolism; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D006801:Humans; D020287:In Situ Nick-End Labeling; D047029:Lactams, Macrocyclic; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D017828:Rifabutin / Q000031:analogs & derivatives; D013739:Testosterone / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology
D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D012739:Gonadal Steroid Hormones; D047029:Lactams, Macrocyclic; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D011809:Quinones; D012333:RNA, Messenger; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C096429:L 709049; D017828:Rifabutin; D013739:Testosterone; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D020169:Caspases