Diabetes mellitus and risk of prostate cancer in the health professionals follow-up study.

History of diabetes may be associated with decreased prostate cancer (PCa) risk. Published studies have not always accounted for time since diabetes diagnosis or confounding and effect modification by lifestyle factors. The authors investigated the relationship between diabetes and PCa risk in men in the Health Professionals Follow-Up Study from 1986 to 2004. During that time, 4,511 new PCa cases were identified. Multivariate hazard ratios (HR) were estimated using Cox regression. The HR of PCa comparing men with vs. without diabetes was 0.83 and 95% confidence interval (CI): 0.74, 0.94. PCa risk was not reduced in the first year after diabetes diagnosis (HR: 1.30, CI: 0.97, 1.72), was lower for men diagnosed for 1-6 years (HR: 0.82, CI: 0.66, 1.02), and was even lower for men who had been diagnosed for 6-15 (HR: 0.75, CI: 0.61, 0.93) or >15 years (HR: 0.78, CI: 0.63, 0.96). Reduced PCa risk was stronger in men diagnosed before 1994 (pre-PSA era) vs. after 1994. The authors also demonstrated that obese and diabetic men had a lower HR for PCa than those who were either not obese and diabetic or obese and non-diabetic. Results are consistent with the hypothesis that diabetes is associated with reduced PCa risk. Potential biological mechanisms are discussed.

Randomized trial of a clinic-based weight loss intervention in cancer survivors.

BACKGROUND: This trial examined the efficacy of a clinic-based weight loss intervention in cancer survivors. METHODS: This single-center phase II trial randomized survivors of solid tumors and hematologic malignancies to a 15-week group-based weight loss intervention that included caloric restriction and physical activity (n = 30) or a wait-list control intervention (n = 30). The primary study outcome was body mass. Secondary study outcomes included body composition using dual-energy X-ray absorptiometry, physical fitness using the 6-min walk test (6MWT), and concentrations of serum biomarkers. RESULTS: Participants in the intervention group lost 5.6 ± 4.4% of baseline weight (4.6 ± 3.9 kg), whereas participants in the control group gained 0.2 ± 2.4% of baseline weight (0.2 ± 2.0 kg); intervention effect - 5.8% (95% CI - 7.8, - 3.8); - 4.8 kg (95% CI - 6.6, - 3.0); P = 0.0001. A larger proportion of participants in the intervention group lost ≥ 5% of baseline weight compared to the control group (43 vs 0%; P < 0.0001). The intervention led to reductions in fat mass (- 3.2 ± 0.7 kg; P < 0.0001), improvements in physical fitness (an increase of 22.6 ± 10.8 m on 6MWT; P = 0.03), and reductions in concentrations of insulin (- 7.7 ± 3.5 µU/mL; P = 0.004) and leptin (- 7.3 ± 4.0 ng/mL; P = 0.04). CONCLUSION: A 15-week clinic-based weight loss intervention resulted in significant weight loss and improvements in body composition, physical fitness, and concentrations of serum biomarkers in cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Weight loss programs provide a number of benefits for cancer survivors; survivors should inquire about the availability of lifestyle programs offered at their cancer center and within their local communities.

A meta-analysis of diabetes mellitus and the risk of prostate cancer.

BACKGROUND: Studies investigating the association between diabetes mellitus and prostate cancer have reported inconsistent findings. We examined this association by conducting a detailed meta-analysis of the studies published on the subject. METHODS: MEDLINE and EMBASE databases and bibliographies of retrieved articles were searched. Studies investigating the relationship between diabetes mellitus and prostate cancer were included in the meta-analysis. Potential sources of heterogeneity between studies were explored and publication bias was evaluated. Pooled relative risk (RR) was calculated using the random-effects model. Numerous relevant subgroup analyses were also done. RESULTS: We included 19 studies, published between 1971 and 2005, in the meta-analysis and found an inverse association between diabetes mellitus and prostate cancer [RR, 0.84, 95% confidence interval (CI), 0.76-0.93, P for heterogeneity

Hormonal profile of diabetic men and the potential link to prostate cancer.

OBJECTIVE: Previous studies suggest men with diabetes may be at reduced risk for prostate cancer as compared to men without diabetes. To investigate potential biological mechanisms, hormonal profiles of diabetic men and non-diabetic controls were compared. METHODS: In the Health Professionals Follow-Up Study, plasma levels of C-peptide, testosterone, sex-hormone binding globulin, insulin-like growth factor-1, and insulin-like growth factor binding protein-3 were determined in 171 diabetic men and 3,001 non-diabetic controls. Multiple linear regression analysis was conducted and least square means were calculated for hormones of interest. RESULTS: Plasma levels of several hormones either < or =1, 1.1-6, 6.1-14.9, or > or =15 years after diagnosis with diabetes were examined. As time since diabetes diagnosis increased, plasma levels of C-peptide and IGFBP-3 significantly decreased (p for trend: C-peptide =.05, IGFBP-3 =.03). While testosterone and SHBG levels both significantly increased with increasing time since diabetes diagnosis (p for trend: testosterone =.02, SHBG =.002), the ratio of testosterone to SHBG decreased, suggesting a reduction in bioavailable testosterone. Plasma IGF-1 levels were lower in diabetics than non-diabetics, but no significant time trend was noted. CONCLUSION: This study of hormonal profiles of diabetic versus non-diabetic men identified changes in diabetic men that may be consistent with reduced prostate cancer risk.

A novel p53-binding domain in CUL7.

CUL7 is a member of the cullin RING ligase family and forms an SCF-like complex with SKP1 and FBXW8. CUL7 is required for normal mouse embryonic development and cellular proliferation, and is highly homologous to PARC, a p53-associated, parkin-like cytoplasmic protein. We determined that CUL7, in a manner similar to PARC, can bind directly to p53 but does not affect p53 expression. We identified a discrete, co-linear domain in CUL7 that is conserved in PARC and HERC2, and is necessary and sufficient for p53-binding. The presence of p53 stabilized expression of this domain and we demonstrate that this p53-binding domain of CUL7 contributes to the cytoplasmic localization of CUL7. The results support the model that p53 plays a role in regulation of CUL7 activity.

Simian virus 40 large T antigen's association with the CUL7 SCF complex contributes to cellular transformation.

Simian virus 40 large T antigen (T Ag) is capable of immortalizing and transforming rodent cells. The transforming activity of T Ag is due in large part to perturbation of the tumor suppressor proteins p53 and the retinoblastoma (pRB) family members. Inactivation of these tumor suppressors may not be sufficient for T Ag-mediated cellular transformation. It has been shown that T Ag associates with an SCF-like complex that contains a member of the cullin family of E3 ubiquitin ligases, CUL7, as well as SKP1, RBX1, and an F-box protein, FBXW8. We identified T Ag residues 69 to 83 as required for T Ag binding to the CUL7 complex. We demonstrate that delta69-83 T Ag, while it lost its ability to associate with CUL7, retained binding to p53 and pRB family members. In the presence of CUL7, wild-type (WT) T Ag but not delta69-83 T Ag was able to induce proliferation of mouse embryo fibroblasts, an indication of cellular transformation. In contrast, WT and delta69-83 T Ag enabled mouse embryo fibroblasts to proliferate to similarly high densities in the absence of CUL7. Our data suggest that, in addition to p53 and the pRB family members, T Ag serves to bind to and inactivate the growth-suppressing properties of CUL7. In addition, these results imply that, at least in the presence of T Ag, CUL7 may function as a tumor suppressor.

Cul7/p185/p193 binding to simian virus 40 large T antigen has a role in cellular transformation.

Simian virus 40 large T antigen (TAg) is a viral oncoprotein that can promote cellular transformation. TAg's transforming activity results in part by binding and inactivating key tumor suppressors, including p53 and the retinoblastoma protein (pRb). We have identified a TAg-associated 185-kDa protein that has significant homology to the cullin family of E3 ubiquitin ligases. TAg binds to an SCF-like complex that contains p185/Cul7, Rbx1, and the F box protein Fbw6. This SCF-like complex binds to an N-terminal region of TAg. Several p185/Cul7-binding-deficient mutants of TAg were generated that retained binding to pRb and p53 and were capable of overcoming Rb-mediated repression of E2F transcription. Despite binding to pRb and p53, these p185/Cul7-binding-defective mutants of TAg were unable to transform primary mouse embryo fibroblasts. Cells expressing p185/Cul7-binding-defective mutants of TAg were unable to grow to high density or grow in an anchorage-independent manner as determined by growth in soft agar. Considering the significance of other TAg-interacting proteins in regulation of the cell cycle, p185/Cul7 may also regulate an important growth control pathway.

Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis.

Cul1, a member of the cullin ubiquitin ligase family, forms a multiprotein complex known as SCF and plays an essential role in numerous cellular and biological activities. A Cul1 homologue, p185 (Cul7), has been isolated as an simian virus 40 large T antigen-binding protein. To understand the physiological role of p185, we generated mice lacking p185. p185-/- embryos are runted and die immediately after birth because of respiratory distress. Dermal and hypodermal hemorrhage is detected in mutant embryos at late gestational stage. p185-/- placentas show defects in the differentiation of the trophoblast lineage with an abnormal vascular structure. We demonstrate that p185 forms an SCF-like complex with Skp1, Rbx1, Fbw6 (Fbx29), and FAP68 (FAP48, glomulin). FAP68 has recently been identified as a gene responsible for familial glomuvenous malformation. These results suggest that p185 forms a multiprotein complex and plays an important role in vascular morphogenesis.