Indole-3-carbinol inhibits protein kinase B/Akt and induces apoptosis in the human breast tumor cell line MDA MB468 but not in the nontumorigenic HBL100 line.
We have identified a new target for the chemopreventive dietary agent indole-3-carbinol (13C) in the antiapoptotic signaling pathway involving phosphatidylinositol 3'-kinase and protein kinase B (PKB)/Akt. 13C inhibited phosphorylation and activation of PKB in the tumor-derived breast cell line MDA MB468, but not in the immortalized breast line HBL100. We propose that this cell type-specific response to 13C contributes to the differential induction of apoptosis and sensitivity to growth inhibition of the two cell lines (approximate IC50 = 30 microM for the MDA MB468 line, compared with 120 microM for the HBL100 line). 13C only induced apoptosis in the MDA MB468 cell line, but at higher doses, it increased necrosis in the HBL100 line. The tumor cell line was also markedly less able to recover when 13C was removed from the culture medium. Downstream of PKB, 13C decreased nuclear factor kappaB DNA binding, independently of an effect on IkappaB kinase, in the MDA MB468 cell line only. The tumor suppressor PTEN, which prevents phosphorylation and activation of PKB, was expressed in HBL100 cells but was not detected in MDA MB468 cells. In corroboration of the results obtained with the breast cell lines, 13C decreased phospho-PKB levels and induced apoptosis in the prostate cell line LNCaP, which expresses very low levels of PTEN, but did not do so in PTEN-positive DU145 cells. 13C did not affect PTEN levels in any cell line. This is the first study to report a differential mechanistic response of tumor-derived and nontumorigenic cell lines and of PTEN high- and low-expressing cells to 13C and indicates a promising chemopreventive role for 13C against estrogen receptor-alpha-negative, aggressive-phenotype breast tumors.
Howells
Lynne M
LM
Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, Leicester LE1 7RH, United Kingdom.
Gallacher-Horley
Barbara
B
Houghton
Catherine E
CE
Manson
Margaret M
MM
Hudson
E Ann
EA
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D016588:Anticarcinogenic Agents; D004273:DNA, Neoplasm; D051550:I-kappa B Kinase; D007211:Indoles; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010718:Phosphatidylserines; D010744:Phosphoric Monoester Hydrolases; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C016517:indole-3-carbinol; C494918:AKT1 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C494929:PTEN protein, human