TY - JOUR
T1 - E2F1 expression in LNCaP prostate cancer cells deregulates androgen dependent growth, suppresses differentiation, and enhances apoptosis
AU - Libertini, Stephen J.
AU - Tepper, Clifford G
AU - Guadalupe, Moraima
AU - Lu, Ying
AU - Asmuth, David
AU - Mudryj, Maria
PY - 2006/1/1
Y1 - 2006/1/1
N2 - INTRODUCTION AND OBJECTIVES. 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. CONCLUSION. 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.
AB - INTRODUCTION AND OBJECTIVES. 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. CONCLUSION. 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.
KW - Apoptosis
KW - Differentiation
KW - E2F
KW - Growth arrest
KW - Prostate cancer
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U2 - 10.1002/pros.20314
DO - 10.1002/pros.20314
M3 - Article
C2 - 16114066
AN - SCOPUS:29344474660
VL - 66
SP - 70
EP - 81
JO - Prostate
JF - Prostate
SN - 0270-4137
IS - 1
ER -