High Density Lipoproteins Inhibit Oxidative Stress-Induced Prostate Cancer Cell Proliferation

Recent evidence suggests that oxidative stress can play a role in the pathogenesis and the progression of prostate cancer (PCa). Reactive oxygen species (ROS) generation is higher in PCa cells compared to normal prostate epithelial cells and this increase is proportional to the aggressiveness of the phenotype. Since high density lipoproteins (HDL) are known to exert antioxidant activities, their ability to reduce ROS levels and the consequent impact on cell proliferation was tested in normal and PCa cell lines. HDL significantly reduced basal and H2O2-induced oxidative stress in normal, androgen receptor (AR)-positive and AR-null PCa cell lines. AR, scavenger receptor BI and ATP binding cassette G1 transporter were not involved. In addition, HDL completely blunted H2O2-induced increase of cell proliferation, through their capacity to prevent the H2O2-induced shift of cell cycle distribution from G0/G1 towards G2/M phase. Synthetic HDL, made of the two main components of plasma-derived HDL (apoA-I and phosphatidylcholine) and which are under clinical development as anti-atherosclerotic agents, retained the ability of HDL to inhibit ROS production in PCa cells. Collectively, HDL antioxidant activity limits cell proliferation induced by ROS in AR-positive and AR-null PCa cell lines, thus supporting a possible role of HDL against PCa progression

Air Pollution: Another Threat to HDL Function

Epidemiological studies have consistently demonstrated a positive association between exposure to air pollutants and the incidence of cardiovascular disease, with the strongest evidence for particles with a diameter 2.5). Therefore, air pollution has been included among the modifiable risk factor for cardiovascular outcomes as cardiovascular mortality, acute coronary syndrome, stroke, heart failure, and arrhythmias. Interestingly, the adverse effects of air pollution are more pronounced at higher levels of exposure but were also shown in countries with low levels of air pollution, indicating no apparent safe threshold. It is generally believed that exposure to air pollution in the long-term can accelerate atherosclerosis progression by promoting dyslipidemia, hypertension, and other metabolic disorders due to systemic inflammation and oxidative stress. Regarding high density lipoproteins (HDL), the impact of air pollution on plasma HDL-cholesterol levels is still debated, but there is accumulating evidence that HDL function can be impaired. In particular, the exposure to air pollution has been variably associated with a reduction in their cholesterol efflux capacity, antioxidant and anti-inflammatory potential, and ability to promote the release of nitric oxide. Further studies are needed to fully address the impact of various air pollutants on HDL functions and to elucidate the mechanisms responsible for HDL dysfunction

Body Mass Index Modulates the Impact of Short-Term Exposure to Air Particulate Matter on High-Density Lipoprotein Function

Air particulate matter (PM) exposure has been associated with increased cardiovascular risk, especially in obesity. By triggering inflammation and oxidative stress, PM could impact atheroprotection by high-density lipoproteins (HDL). The aim of the study was to assess the relationship between short-term exposure to PM and HDL function, and the modifying effect of body mass index (BMI). Daily exposures to PM10 and PM2.5 of 50 subjects with overweight/obesity and 41 healthy volunteers with BMI 2 were obtained from fixed monitoring stations. HDL function was assessed as promotion of nitric oxide (NO) release by endothelial cells and reduction in cholesterol in macrophages. HDL-induced NO release progressively declined with the increase in BMI. No association was found between HDL function and PM exposure, but a modifying effect of BMI was observed. The positive association between PM10 exposure at day −1 and NO production found at normal BMI values was lost in participants with higher BMI. Similar results were obtained for the reduction in macrophage cholesterol. The loss of the compensatory response of HDL function to PM exposure at increasing BMI levels could contribute to the endothelial dysfunction induced by PM and help to explain the susceptibility of subjects with obesity to air pollution

HDL‐mediated reduction of cholesterol content inhibits the proliferation of prostate cancer cells induced by LDL: Role of ABCA1 and proteasome inhibition

High-density lipoproteins (HDL) are well known for their atheroprotective function, mainly due to their ability to remove cell cholesterol and to exert antioxidant and anti-inflammatory activities. Through the same mechanisms HDL could also affect the development and progression of tumors. Cancer cells need cholesterol to proliferate, especially in hormone-dependent tumors, as prostate cancer (PCa). Aim of the study was to investigate the ability of HDL to modulate cholesterol content and metabolism in androgen receptor (AR)-positive and AR-null PCa cell lines and the consequences on cell proliferation. HDL inhibited colony formation of LNCaP and PC3 cells. HDL reduced cell cholesterol content and proliferation of LNCaP cells loaded with low-density lipoproteins but were not effective on PC3 cells. Here, the expression of the ATP-binding cassette transporter A1 (ABCA1) was markedly reduced due to proteasome degradation. Bortezomib, a proteasome inhibitor, restored ABCA1 expression and HDL ability to promote cholesterol removal from PC3; consequently, HDL inhibited the proliferation of PC3 cells induced by LDL only after bortezomib pre-treatment. In conclusion, the antiproliferative activity of HDL on AR-positive and AR-null PCa cells also rely on cholesterol removal, a process in which the ABCA1 transporter plays a key role