E2F1 expression in LNCaP prostate cancer cells deregulates androgen dependent growth, suppresses differentiation, and enhances apoptosis

Stephen J. Libertini, Clifford G Tepper, Moraima Guadalupe, Ying Lu, David Asmuth, Maria Mudryj

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)70-81
Number of pages12
JournalProstate
Volume66
Issue number1
DOIs
StatePublished - Jan 1 2006

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Androgens
Prostatic Neoplasms
Apoptosis
Growth
Western Blotting
Tumor Suppressor Protein p14ARF
Caspase 7
Cyclin E
Caspase 9
Caspase 8
Phosphopyruvate Hydratase
Androgen Receptors
Etoposide
Caspase 3
Prostate
Flow Cytometry
Hormones
Staining and Labeling
Neoplasms
Proteins

Keywords

  • Apoptosis
  • Differentiation
  • E2F
  • Growth arrest
  • Prostate cancer

ASJC Scopus subject areas

  • Urology

Cite this

E2F1 expression in LNCaP prostate cancer cells deregulates androgen dependent growth, suppresses differentiation, and enhances apoptosis. / Libertini, Stephen J.; Tepper, Clifford G; Guadalupe, Moraima; Lu, Ying; Asmuth, David; Mudryj, Maria.

In: Prostate, Vol. 66, No. 1, 01.01.2006, p. 70-81.

Research output: Contribution to journalArticle

Libertini, Stephen J. ; Tepper, Clifford G ; Guadalupe, Moraima ; Lu, Ying ; Asmuth, David ; Mudryj, Maria. / E2F1 expression in LNCaP prostate cancer cells deregulates androgen dependent growth, suppresses differentiation, and enhances apoptosis. In: Prostate. 2006 ; Vol. 66, No. 1. pp. 70-81.
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AU - Tepper, Clifford G

AU - Guadalupe, Moraima

AU - Lu, Ying

AU - Asmuth, David

AU - Mudryj, Maria

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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.

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