4-hydroxy-2-nonenal and Prostatic-Neoplasms

An oxidative degradation product of the polyunsaturated fatty acids, 4-hydroxynonenal (4-HNE), is of particular interest in cancer research due to its concentration-dependent pleiotropic activities affecting cellular antioxidants, metabolism, and growth control. Although an increase in oxidative stress and lipid peroxidation was already associated with prostate cancer progression a few decades ago, the knowledge of the involvement of 4-HNE in prostate cancer tumorigenesis is limited. This study investigated the appearance of 4-HNE-protein adducts in prostate cancer tissue by immunohistochemistry using a genuine 4-HNE monoclonal antibody. Plasma samples of the same patients and samples of the healthy controls were also analyzed for the presence of 4-HNE-protein adducts, followed by metabolic profiling using LC-ESI-QTOF-MS and GC-EI-Q-MS. Finally, the analysis of the metabolic pathways affected by 4-HNE was performed. The obtained results revealed the absence of 4-HNE-protein adducts in prostate carcinoma tissue but increased 4-HNE-protein levels in the plasma of these patients. Metabolomics revealed a positive association of different long-chain and medium-chain fatty acids with the presence of prostate cancer. Furthermore, while linoleic acid positively correlated with the levels of 4-HNE-protein adducts in the blood of healthy men, no correlation was obtained for cancer patients indicating altered lipid metabolism in this case. The metabolic pathway of unsaturated fatty acids biosynthesis emerged as significantly affected by 4-HNE. Overall, this is the first study linking 4-HNE adduction to plasma proteins with specific alterations in the plasma metabolome of prostate cancer patients. This study revealed that increased 4-HNE plasma protein adducts could modulate the unsaturated fatty acids biosynthesis pathway. It is yet to be determined if this is a direct result of 4-HNE or whether they are produced by the same underlying mechanisms. Further mechanistic studies are needed to grasp the biological significance of the observed changes in prostate cancer tumorigenesis.

Topics: Aldehydes; Biomarkers; Carcinogenesis; Fatty Acids, Unsaturated; Humans; Lipid Peroxidation; Male; Prostatic Neoplasms; Proteins

To investigate the expressions of HSF1 and tetra-hydroxynonene (4-HNE) in prostate cancer (PCa) tissue and their clinical significance.. Using the immunohistochemical method, we detected the expressions of HSF1 and 4-HNE in the prostatic tissues of 50 cases of PCa and another 50 cases of BPH, and analyzed the relationship of the two expressions with Gleason grade.. The positive expression level of HSF1 was dramatically higher in the highly, moderately and lowly differentiated PCa than in the BPH tissue (37.5%, 50.0% and 75.0% vs 4.0%, P = 0.001) and showed statistically significant difference among different Gleason grades (P = 0.025), so was that of 4-HNE (81.3%, 92.9% and 100.0% % vs 6.0%, P = 0.001), also with statistically significant difference among different Gleason grades (P = 0.029). There was a positive correlation between the expression of HSF1 and that of 4-HNE in the PCa tissue (r = 0.947, P = 0.001).. The overexpressions of HSF1 and 4-HNE are related to the Gleason grades of prostate cancer, which can be used as an new biological marker with important reference value for assessing the malignancy of prostate cancer.

Topics: Aldehydes; Biomarkers, Tumor; Heat Shock Transcription Factors; Humans; Male; Neoplasm Grading; Phenotype; Prostatic Neoplasms

To investigate the expressions of glutathione S-transferase (GSTP1) and tetra-hydroxynonenal (4-HNE) in prostate cancer (PCa) and their clinical significance.. We determined the expressions of GSTP1 and 4-HNE in 40 patients with PCa and another 42 with benign prostatic hyperplasia (BPH) by immunohistochemistry and analyzed their relationship with Gleason grades.. The expression rate of GSTP1 was 92.9% in the BPH tissue, and those in the highly, moderately, and lowly differentiated PCa tissues were 58.3%, 20.0%, and 16.7%, respectively, significantly higher in the BPH than in the PCa group (P <0.01). However, the positive rate of 4-HNE was only 5.0% in the BPH tissue, markedly lower than 91.6%, 100.0%, and 100.0% in the highly, moderately, and lowly differentiated PCa tissues (P <0.01). There was a negative correlation between the expression of GSTP1 and that of 4-HNE in the PCa tissue (r = －2.73, P <0.01).. Expression deletion of GSTP1 and high expression of 4-HNE may play an important role in the progression of prostate cancer.. 目的： 探讨谷胱甘肽S转移酶P1（GSTP1）和四羟基壬烯(4-HNE)在前列腺癌组织中的表达及其临床意义。方法： 采用免疫组化方法检测40例前列腺癌组织及42例BPH组织中GSTP1和4-HNE 的表达，分析GSTP1和4-HNE的表达与Gleason分级之间的关系。结果： GSTP1在BPH组织中为高表达(92.9%)，40例前列腺癌组织中GSTP1表达率在高、中、低分化癌中分别为58.3%、20.0%、16.7%，呈下降趋势，两组GSTP1表达差异有统计学意义（P<0.01）。4-HNE在前列腺增生组织中阳性表达率较低，仅为5.0%。40例前列腺癌组织中4-HNE高表达，在高、中、低分化癌中分别为91.6%、100.0%、100.0%，呈明显上升趋势，两组4-HNE表达差异有统计学意义（P<0.01）。前列腺癌组织中GSTP1和4-HNE阳性表达呈负相关（r=－2.73，P<0.01）。结论: GSTP1表达缺失和4-HNE的高表达，可能在前列腺癌的进展中起重要作用。.

Topics: Aldehydes; Disease Progression; Glutathione S-Transferase pi; Humans; Immunohistochemistry; Male; Neoplasm Grading; Neoplasm Proteins; Prostatic Hyperplasia; Prostatic Neoplasms

Histone deacetylase inhibitors (HDACIs) are promising antineoplastic agents for the treatment of cancer. Here we report that the lipid peroxidation end product 4-hydroxynonenal (HNE) significantly potentiates the anti-tumor effects of the HDAC inhibitor panobinostat (LBH589) in the PC3 prostate cancer cell model. Panobinostat and HNE inhibited proliferation of PC3 cells and the combination of the two agents resulted in a significant combined effect. Cell cycle analysis revealed that both single agents and, to a greater extent, their combined treatment induced G2/M arrest, but cell death occurred in the combined treatment only. Furthermore, HNE and, to a greater extent, the combined treatment induced dephosphorylation of Cdc2 leading to progression into mitosis as confirmed by α-tubulin/DAPI staining and phospho-histone H3 (Ser10) analysis. To evaluate possible induction of DNA damage we utilized the marker phosphorylated histone H2A.X. Results showed that the combination of panobinostat and HNE induced significant DNA damage concomitant with the mitotic arrest. Then, by using androgen receptor (AR)-expressing PC3 cells we observed that the responsiveness to HNE and panobinostat was independent of the expression of functional AR. Taken together, our data suggest that HNE potentiates the antitumoral effect of the HDACI panobinostat in prostate cancer cells.

Topics: Acetylation; Aldehydes; Apoptosis; Blotting, Western; Cell Cycle; Cysteine Proteinase Inhibitors; DNA Damage; Flow Cytometry; Fluorescent Antibody Technique; Glutathione; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Indoles; Lipid Peroxidation; Male; Panobinostat; Phosphorylation; Prostatic Neoplasms; Receptors, Androgen; Tumor Cells, Cultured

4-Hydroxynonenal (HNE) is an end product of lipoperoxidation with antiproliferative and proapoptotic properties in various tumors. Here we report a greater sensitivity to HNE in PC3 and LNCaP cells compared to DU145 cells. In contrast to PC3 and LNCaP cells, HNE-treated DU145 cells showed a smaller reduction in growth and did not undergo apoptosis. In DU145 cells, HNE did not induce ROS production and DNA damage and generated a lower amount of HNE-protein adducts. DU145 cells had a greater GSH and GST A4 content and GSH/GST-mediated HNE detoxification. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a regulator of the antioxidant response. Nrf2 protein content and nuclear accumulation were higher in DU145 cells compared to PC3 and LNCaP cells, whereas the expression of KEAP1, the main negative regulator of Nrf2 activity, was lower. Inhibition of Nrf2 expression with specific siRNA resulted in a reduction in GST A4 expression and GS-HNE formation, indicating that Nrf2 controls HNE metabolism. In addition, Nrf2 knockdown sensitized DU145 cells to HNE-mediated antiproliferative and proapoptotic activity. In conclusion, we demonstrated that increased Nrf2 activity resulted in a reduction in HNE sensitivity in prostate cancer cells, suggesting a potential mechanism of resistance to pro-oxidant therapy.

Topics: Aldehydes; Apoptosis; Cell Growth Processes; Cell Line, Tumor; Cell Nucleus; DNA Damage; Gene Expression Regulation; Glutathione Transferase; Humans; Lipid Peroxidation; Male; NF-E2-Related Factor 2; Prostatic Neoplasms; Reactive Oxygen Species; RNA, Small Interfering