Effect of Bcl‐2 overexpression in human prostate cancer cells in vitro and in vivo

Abstract

Background: Cancer cells often develop mechanisms to resist apoptosis and the extent of such anti-apoptotic ability has been shown to parallel tumor progression in various malignancies. Among various molecules implicated in regulating apoptosis pathway, bcl-2 and its family members are best characterized. Methods:To investigate the effect of bcl-2-mediated anti-apoptotic ability on tumor growth and progression in prostate cancer, a cell line overexpressing bcl-2 (LNCaP/bcl-2) was established by genetically engineering a prostate cancer cell line LNCaP. Tumor growth of LNCaP/bcl-2 was compared with the parental cell line in vitro and in vivo.Results: LNCaP/bcl-2 cells show resistance to apoptosis caused by nutrient deprivation and did not arrest when cultured in serum-free or androgen-free medium, while parental LNCaP cells or LNCaP cells transfected with the vector only (LNCaP/control) underwent extensive apoptosis on nutrient deprivation and sustained growth suppression in serum-free or androgen-free medium. When injected subcutaneously into nude mice, tumors deriving from LNCaP/bcl-2 cells grew faster compared with LNCaP/control for about 3 weeks (P = 0.02), but this effect was not evident after 5 weeks. Upon castration, the control tumors regressed but LNCaP/bcl-2-derived tumors showed resistance, as was previously reported. Conclusions: These data confirm the notion that anti-apoptotic function of bcl-2 is oncogenic and confers resistance to androgen deprivation and also indicate that it may also play a critical role in earlier stages of tumorigenesis.

The Significance of Key Regulators of Apoptosis in the Development and Prognosis of Prostate Carcinoma. I. Proteins of the BCL-2 Family and Protein P53

“…In addition, Bcl-2 expression in prostate tumour lines is associated with lowered apoptotic response after treatment with different chemotherapeutics, ionising radiation and resistance to apoptosis caused by nutritional deprivation. These data confirm that the antiapoptotic function of Bcl-2 is oncogenic and contributes to the resistance to antiandrogen treatment 18,39,40 . Baltaci et al determined the occurrence of Bcl-2 protein expression in low and in high grade prostatic intraepithelial neoplasia (PIN) lesions and investigated thus the role of Bcl-2 in tumourigenesis of the prostate.…”

Antitumor Effects of a Novel Small Molecule Targeting PCNA Chromatin Association in Prostate Cancer

“…C, the surviving fraction was calculated using the formula: surviving fraction ¼ (plating efficiency of treated/plating efficiency of control) Â 100. Ã , P < 0.05; ÃÃ , P < 0.01. to apoptotic stimuli both in vitro and in vivo and allow the normally androgen-sensitive LNCaP cells to form tumors in an androgen-depleted host, thus promoting progression of prostate cancer to CRPC (37,38). Therefore, the observed decrease in Bcl-2 expression upon treatment with PCNA-I1 suggests that these cells may be sensitized to apoptosis.…”

Bcl-2 and Bcl-xL differentially protect human prostate cancer cells from induction of apoptosis by melanoma differentiation associated gene-7, mda-7/IL-24

“…Bcl-2 expression in tissues has been evaluated as an indicator for poor prognosis in prostate carcinoma (Bauer et al, 1996;Keshgegian et al, 1998;Sullivan et al, 1998;Baif et al, 1999). Moreover, Bcl-2 expression is augmented following androgen ablation and is correlated with the progression of prostate cancer from androgen dependence to androgen independence (McDonnell et al, 1992;McConkey et al, 1996;Beham et al, 1998;Kajiwara et al, 1999). Bcl-x L overexpression has been found to correlate with resistance to druginduced apoptosis in prostate cancer cells (Liu and Stein, 1997;Amundson et al, 2000;Lebedeva et al, 2000;Li et al, 2001).…”