Elevated Levels of Apoptosis Regulator Proteins P53 and BCL-2 are Independent Prognostic Biomarkers in Surgically Treated Clinically Localized Prostate Cancer

Bauer, John J.; Sesterhenn, Isabell A.; Mostofi, F. K.; McLeod, David G.; Srivastava, Shiv; Moul, Judd W.

doi:10.1016/s0022-5347(01)65641-6

Cited by 205 publications

(66 citation statements)

References 15 publications

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“…The Bcl-2 family and caspase-3 are important regulators of apoptosis. Several studies have shown that elevated expression of Bcl-2 in prostate cancer cells confers androgen resistance, particularly in advanced disease, and it may facilitate progression to androgen independence [20][21][22]. Bcl-2 is part of an expanding family of apoptosisregulatory molecules, which may act as either death antagonists (Bcl-2, Bcl-xl and Mcl-1) or death agonists (Bax, Bak, Bcl-xS, Bad and Bid).…”

Section: Discussionmentioning

confidence: 99%

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

Xia¹,

Luo²,

Wang³

2009

Asian J Androl

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Abstractp27 is a cyclin-dependent kinase inhibitor that regulates the progression of cells from G 1 to S phase of the cell cycle. Loss of p27 has been associated with disease progression and with an unfavourable outcome in prostate cancer. In this study, we investigated whether exogenous p27 expression in the human androgen-independent prostate cancer PC3 cell line had any effect on cell growth, and we studied the molecular mechanisms involved. p27 expression was restored in PC3 cells by plasmid delivery. Cell proliferation and apoptosis were assessed in PC3 cells transfected with p27. We also investigated the effects of p27 on the epidermal growth factor receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway in PC3 cells. By restoring p27 expression in PC3 cells, we observed that p27 reduced proliferation and induced arrest in G 0 /G 1 phase. Moreover, p27-transfected PC3 cells underwent apoptosis, as shown by flow cytometric analysis and western blotting analysis of Bcl-2, Bax, Bad, caspase-3 and poly(ADP-ribose)polymerase expression. Furthermore, the p27-induced anti-tumour action correlated with inhibition of the EGFR/PI3K/Akt signalling pathway, as confirmed by western blotting analysis and densitometry of EGFR, PI3K (p85), Akt and p-Akt S473 expression. Our results suggest that exogenous expression of p27 inhibits the proliferation of PC3 cells through induction of G 1 arrest and apoptosis, and this process correlates with inhibition of the EGFR/PI3K/Akt signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

Xia¹,

Luo²,

Wang³

2009

Asian J Androl

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“…Expression of p53 has been shown by various studies to have prognostic significance in human prostate cancer [20][21][22][23][24][25][26][27][28] (Table 5), whereas other studies in patients with clinically localized prostate cancer have shown no predictive value [29][30] (Table 5). p53 is a tumour suppressor protein that may mutate and accumulate within malignant cells with progression of prostate cancer, particularly in the more advanced stages of the disease.…”

Section: Discussionmentioning

confidence: 99%

Utility of tissue microarrays for profiling prognostic biomarkers in clinically localized prostate cancer: the expression of BCL-2, E-cadherin, Ki-67 and p53 as predictors of biochemical failure after radical prostatectomy with nested control for clinical and pathological risk factors

Nariculam¹,

Freeman²,

Bott³

et al. 2008

Asian J Androl

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“…However, resistant clones exist because of the overexpression of the antiapoptotic protein Bcl-2, which is inherent and/or results from prolonged exposure to cytotoxic treatment conditions (Tang and Porter, 1997;Autorino et al, 2003;Shaffer and Scher, 2003). Bcl-2 overexpression is frequently found in both primary and metastatic human prostate cancers (Bauer et al, 1996;Krajewska et al, 1996). Primary tumors that overexpress Bcl-2 exhibit a high Gleason score and a high rate of cancer recurrence after radical prostatectomy (Krajewska et al, 1996;Hering et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor

Chervin

Nie

et al. 2006

Oncogene

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Bcl-2 overexpression is an important mechanism underlying the aggressive behavior of prostate cancer cells and their resistance to radio-or chemotherapy. HA14-1, a recently discovered organic Bcl-2 inhibitor, potently induces apoptosis in various human cancer cells. Sequential exposure of radioresistant LNCaP (wild-type (wt) p53), LNCaP/Bcl-2 (wt p53) and PC3 (mutant p53) prostate cancer cells to a minimally cytotoxic concentration of 10 lM HA14-1 for 1 h followed by 1-6 Gy gamma radiation, resulted in a highly synergistic (combination index o1.0) induction of cell death as determined by an apoptosis assay at 72 h, and a clonogenicity assay at 12 days, after the initial treatment. The reverse treatment sequence did not cause a synergistic induction of cell death. When compared to individual treatments, cell death induced by the combined treatment was associated with dramatically increased reactive oxygen species (ROS) generation, c-Jun N-terminal kinase (JNK) activation, Bcl-2 phosphorylation, cytochrome c release, caspase-3 activation and DNA fragmentation. Exposure to either 200 lg/ml of the antioxidant alpha-tocopherol or 10 lM JNK inhibitor SP600125 before the combined treatment resulted in decreased activation of JNK and caspase-3 as well as decreased DNA fragmentation. However, treatment with the pancaspase inhibitor carbobenzoxyl-valylalanyl-aspartyl-[O-methyl]-fluoromethylketone before the combined treatment inhibited apoptosis without affecting JNK activation, and this inhibitory effect was enhanced in the presence of alpha-tocopherol or SP600125. Taken together, our results indicate that HA14-1 potently sensitizes radioresistant LNCaP and PC3 cells to gamma radiation, regardless of the status of p53. ROS and JNK are important early signals that trigger both caspasedependent and -independent cell death pathways and contribute to the apoptotic synergy induced by the combined treatments.

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Elevated Levels of Apoptosis Regulator Proteins P53 and BCL-2 are Independent Prognostic Biomarkers in Surgically Treated Clinically Localized Prostate Cancer

Abstract: p53 and bcl-2 appear to be important biomarkers that predict recurrence in clinically localized PC after RP.

Cited by 205 publications

References 15 publications

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

Utility of tissue microarrays for profiling prognostic biomarkers in clinically localized prostate cancer: the expression of BCL-2, E-cadherin, Ki-67 and p53 as predictors of biochemical failure after radical prostatectomy with nested control for clinical and pathological risk factors

Overcoming the radioresistance of prostate cancer cells with a novel Bcl-2 inhibitor

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