E2F1 expression in LNCaP prostate cancer cells deregulates androgen dependent growth, suppresses differentiation, and enhances apoptosis.
OBJECTIVE
To investigate the role of E2F/RB in androgen independent proliferation, differentiation, and sensitivity to apoptotic stimuli of LNCaP prostate cancer cells.


METHODS
The effects of E2F1 overexpression on androgen independent proliferation, differentiation, and apoptotic responses was assessed by flow cytometry, Western blot analysis and staining of nuclei.


RESULTS
Overexpression of E2F1 in LNCaP cells confers resistance to an androgen withdrawal-mediated growth arrest, prevents differentiation, and modifies apoptotic responses. Androgen independent proliferation is associated with a dose dependent elevation of cyclin E. Cells expressing high levels of E2F1 continue to express androgen receptor and have a diminished expression of neuronal specific enolase when cultured in androgen-depleted media. Additionally, E2F1-expressing cells are more sensitive to etoposide-induced apoptosis. Western blot analysis revealed that LNCaP-E2F1 cells have elevated expression of p73, Apaf-1, caspase-3, caspase-7, but expression of caspase-8 and -9, p14(ARF), and Mcl-1, is unaltered.


CONCLUSIONS
This is the first study that describes E2F1-dependent modifications of androgen dependence, differentiation, and sensitivity to apoptotic stimuli in LNCaP cells. Our analysis also identifies a subset of E2F1 targets that are instrumental in altering proliferative, differentiation, and apoptotic properties. Deregulation of the E2F/RB pathway and subsequent modification of key regulatory proteins may promote the development of hormone-refractory prostate tumors.
Libertini
Stephen J
SJ
Veterans Affairs Northern California Health Care System, Mather, and Department of Medical Microbiology and Immunology, University of California, Davis, USA.
Tepper
Clifford G
CG
Guadalupe
Moraima
M
Lu
Ying
Y
Asmuth
David M
DM
Mudryj
Maria
M
D000728:Androgens / Q000494:pharmacology; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000235:genetics*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
D000728:Androgens; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human