Transcription factor AP-1 promotes growth and radioresistance in prostate cancer cells.
Expression of AP-1 proteins has been associated with a more aggressive clinical outcome in prostate cancer. However, their role and regulation by upstream kinase pathways in response to ionizing radiation has remained elusive. Here, we show that constitutive AP-1 activity in prostate cancer cells is dependent on the activities of EGF-R and PI3K. While inhibition of EGF-R is associated with suppression of c-Jun expression and proliferation, inhibition of PI3K pathway suppresses expression of several AP-1 subunits and proliferation, and also sensitizes prostate cancer cells to gamma-radiation. The importance of AP-1 as a mediator of proliferation and radiation responses is demonstrated by the findings that the expression of JunD, Fra-1 and Fra-2 siRNAs in prostate cancer cells suppress these cellular responses. Together, the findings show that AP-1 activity in prostate cancer cells mediates EGF-R and PI3K signalling, is essential for their proliferation, and confers protection against radiation-induced cell death. Thus, its inhibition would be a lucrative target for therapy in this widely increasing cancer type.
Kajanne
Risto
R
Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Miettinen
Päivi
P
Tenhunen
Mikko
M
Leppä
Sirpa
S
D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D024202:Electrophoretic Mobility Shift Assay; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics* / Q000528:radiation effects; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D018808:Transcription Factor AP-1; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors