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Abstract: Macrophages are prominent components of human atherosclerotic lesions and they are believed to accelerate the progression and/or complications of both early and advanced atherosclerotic lesions. We and others have shown that oxidized low-density lipoprotein (oxLDL) induces growth and inhibits apoptosis in murine bone marrow-derived macrophages. In this study, we sought to characterize the oxidative modification of LDL that is responsible for this prosurvival effect. We found that both the modified lipid and the modified protein components of oxLDL can increase the viability of macrophages. The key modification appeared to involve derivatization of amino groups in apoB or in phosphatidylethanolamine by lipid peroxidation products. These reactive oxidation products were primarily unfragmented hydroperoxide- or endoperoxide-containing oxidation products of linoleic acid or arachidonic acid. LC-MS/MS studies showed that some of the arachidonic acid-derived lysine adducts were isolevuglandins that contain lactam and hydroxylactam rings. MS/MS analysis of linoleic acid autoxidation adducts was consistent with 5- or 6-membered nitrogen-containing heterocycles derived from unfragmented oxidation products. The amine modification by oxidation products generated a fluorescence pattern with an excitation maximum at 350nm and emission maximum at 430nm. This is very similar to the fluorescence spectrum of copper-oxidized LDL. [Copyright &y& Elsevier]

Abstract: In castration-resistant prostate cancer (CRPC) many androgen-regulated genes become re-expressed and tissue androgen levels increase despite low serum levels. We and others have recently reported that CRPC tumor cells can de novo synthesize androgens from adrenal steroid precursors or cholesterol and that high levels of progesterone exist in LNCaP tumors after castration serving perhaps as an intermediate in androgen synthesis. Herein, we compare androgen synthesis from [3H-progesterone] in the presence of specific steroidogenesis inhibitors and anti-androgens in steroid starved LNCaP cells and CRPC tumors. Similarly, we compare steroid profiles in LNCaP tumors at different stages of CRPC progression. Steroidogenesis inhibitors targeting CYP17A1 and SRD5A2 significantly altered but did not eliminate androgen synthesis from progesterone in steroid starved LNCaP cells and CRPC tumors. Upon exposure to inhibitors of steroidogenesis prostate cancer cells adapt gradually during CRPC progression to synthesize DHT in a compensatory manner through alternative feed-forward mechanisms. Furthermore, tumors obtained immediately after castration are significantly less efficient at metabolizing progesterone (∼36%) and produce a different steroid profile to CRPC tumors. Optimal targeting of the androgen axis may be most effective when tumors are least efficient at synthesizing androgens. Confirmatory studies in humans are required to validate these findings. [Copyright &y& Elsevier]

Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo . LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice ( P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice ( P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 ( P = 0.016) and SRD5A1 ( P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are likely to be mechanistic drivers behind the observed tumor growth suppression. [ABSTRACT FROM AUTHOR]