Neuroendocrine cells in human prostate over‐express the anti‐apoptosis protein survivin
ABSTRACT Neuroendocrine (NE) differentiation may be related to the growth and progression of prostate cancer, especially androgen-insensitive tumors. Recently the over-expression of a new anti-apoptosis protein, survivin, has attracted attention for its potential implication in many human cancers. The fact that NE cells in prostate are bcl-2 negative prompted us to investigate if the prostatic NE cells over-express survivin.
Double immunohistochemical staining and immunofluorescence of chromogranin A (CgA) and survivin were performed in 57 patients with localized prostate cancer who underwent radical prostatectomy. The terminal deoxynucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method was used for apoptosis detection in three prostate cancer specimens with NE differentiation. The relationship between NE differentiation and clinicopathological characteristics, disease progression as well as patient survival, were analyzed retrospectively.
It was found that NE cells in both benign and malignant prostate tissues over-expressed the anti-apoptosis protein survivin. While apoptosis was detected in non-NE epithelial cells, all NE cells were negative for apoptosis detection. During the period of follow-up, 17 (63%) of 27 patients with NE differentiation had prostate cancer progression, while 12 (40%) of 30 patients without NE differentiation had systemic prostate cancer progression. 10 (37%) of 27 patients with NE differentiation died from prostate cancer during the period of follow up, while 6 (20%) of 30 patients without NE differentiation died from prostate cancer. However, none of these characteristics reached statistical significance, probably because of the small number of cases enrolled.
This study discovers that all the prostatic NE cells express the new anti-apoptosis protein survivin. This provides a strong molecular basis for the hypothesis that NE cells may endure stressful conditions and escape from apoptosis. While our results suggest a trend of NE differentiation with poorer prognosis, the prognosis implication cannot be concluded due to our small sample size.
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ABSTRACT: Cyclin D1/CDK4 activity is upregulated in up to 50% of breast cancers and CDK4 mediated phosphorylation negatively regulates the TGFβ superfamily member Smad3. We sought to determine if CDK4 inhibition and doxorubicin chemotherapy could impact Smad3-mediated cell/colony growth and apoptosis in breast cancer cells. Parental and cyclin D1 overexpressing MCF7 cells were treated with CDK4 inhibitor, doxorubicin, or combination therapy and cell proliferation, apoptosis, colony formation, and expression of apoptotic proteins were evaluated using an MTS assay, TUNEL staining, 3D Matrigel assay, and apoptosis array/immunoblotting. Study cells were also transduced with WT Smad3 or a Smad3 construct resistant to CDK4 phosphorylation (5M) and colony formation and expression of apoptotic proteins were assessed. Treatment with CDK4 inhibitor/doxorubicin combination therapy, or transduction with 5M Smad3, resulted in a similar decrease in colony formation. Treating cyclin D overexpressing breast cancer cells with combination therapy also resulted in the greatest increase in apoptosis, resulted in decreased expression of anti-apoptotic proteins survivin and XIAP, and impacted subcellular localization of pro-apoptotic Smac/DIABLO. Additionally, transduction of 5M Smad3 and doxorubicin treatment resulted in the greatest change in apoptotic protein expression. Collectively, this work showed the impact of CDK4 inhibitor-mediated, Smad3-regulated tumor suppression, which was augmented in doxorubicin-treated cyclin D overexpressing study cells.Cancer biology & therapy 07/2014; 15(10). DOI:10.4161/cbt.29693 · 3.63 Impact Factor
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ABSTRACT: Background: We report on the emergence of a rare and atypical variant of castrate-resistant prostate cancer (CRPC) that is characterised by transformation into poorly differentiated neuroendocrine small-cell carcinoma (NSCC). The existence of this variant was previously described in isolated case reports and small case-studies, but as yet there has been no UK series reported in the literature.Methods: Between January 2010 and January 2014, eight cases were presented in our local multi-disciplinary team meeting having a diagnosis of NSCC arising on a background of prostate cancer treated with androgen deprivation therapy. We performed a retrospective review of the clinical records of these patients, to identify the mode of presentation, diagnostic investigations, pathological characteristics, and subsequent treatment and survival outcomes.Results: The median patient age was 77 years (range, 68 – 84), with a median time interval of 25 months (range, 7 – 83) between the original diagnosis and subsequent transformation to NSCC. The median prostate-specific antigen (PSA) was 4 ng/ml, at presentation. Most patients presented with local progression, combined with high-volume and atypical sites of metastasis (e.g. brain, pancreas and penis). Patients developed a good initial response to platinum-based chemotherapy, but responses were short-lived and prognosis poor, with a median overall survival (OS) of 8 months.Conclusion: Prostate NSCC represents an atypical variant of CRPC with significant therapeutic and prognostic implications. Based on our observations, we have proposed a clinical algorithm for early diagnosis and appropriate management of these patients.Japanese Journal of Clinical Urology 01/2014; 8(1). DOI:10.1177/2051415814534234
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ABSTRACT: Neuroendocrine differentiation (NED) is a process by which prostate cancer cells transdifferentiate into neuroendocrine-like (NE-like) cancer cells. Accumulated evidence suggests that NED is associated with disease progression and therapy resistance in prostate cancer patients. We previously reported that by mimicking a clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces NED in prostate cancer cells. Interestingly, FIR-induced NED constitutes two distinct phases: a radioresistance phase in which a fraction of cells selectively survive during the first two week irradiation, and a neuroendocrine differentiation phase in which surviving cells differenti-ate into NE-like cancer cells during the second two week irradiation. We have also observed increased activation of the transcription factor cAMP response element binding (CREB) protein during the course of FIR-induced NED. To determine whether targeting NED can be explored as a radiosensitization approach, we employed two CREB target-ing strategies, CREB knockdown and overexpression of ACREB, a dominant-negative mutant of CREB, to target both phases. Our results showed that ACREB expression increased FIR-induced cell death and sensitized prostate cancer cells to radiation. Consistent with this, knockdown of CREB also inhibited FIR-induced NED and sensitized prostate cancer cells to radiation. Molecular analysis suggests that CREB targeting primarily increases radiation-induced pre-mitotic apoptosis. Taken together, our results suggest that targeting NED could be developed as a radiosensitization approach for prostate cancer radiotherapy.American Journal of Cancer Research 11/2014; 4(6):850-861. · 3.97 Impact Factor