The "Two-Faced" Effects of Reactive Oxygen Species and the Lipid Peroxidation Product 4-Hydroxynonenal in the Hallmarks of Cancer

Reacytive Oxygen Species (ROS) have long been considered to be involved in the initiation, progression and metastasis of cancer. However, accumulating evidence points to the benefical role of ROS. Moreover, ROS production, leading to apoptosis, is the mechanism by which many chemotherapeutic agents can act. Beside direct actions, ROS elicit lipid peroxidation, leading to the production of 4-hydroxynoneal (HNE). Interestingly, HNE also seems to have a dual behaviour with respect to cancer. In this review we present recent literature data which outline the "two-faced" character of oxidative stress and lipid peroxidation in carcinogenesis and in the hallmarks of cancer

The Role of PPAR Ligands in Controlling Growth-Related Gene Expression and their Interaction with Lipoperoxidation Products

Peroxisome proliferators-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. The three PPAR isoforms (α, γ and β/δ) have been found to play a pleiotropic role in cell fat metabolism. Furthermore, in recent years, evidence has been found regarding the antiproliferative, proapoptotic, and differentiation-promoting activities displayed by PPAR ligands, particularly by PPARγ ligands. PPAR ligands affect the expression of different growth-related genes through both PPAR-dependent and PPAR-independent mechanisms. Moreover, an interaction between PPAR ligands and other molecules which strengthen the effects of PPAR ligands has been described. Here we review the action of PPAR on the control of gene expression with particular regard to the effect of PPAR ligands on the expression of genes involved in the regulation of cell-cycle, differentiation, and apoptosis. Moreover, the interaction between PPAR ligands and 4-hydroxynonenal (HNE), the major product of the lipid peroxidation, has been reviewed

Increase of telomerase activity and hTERT expression in myelodysplastic syndromes

Telomerase enzyme, containing a catalytic subunit, the human telomerase reverse transcriptase (hTERT), and a small integral RNA component, synthesises the telomeres, the ends of eukaryotic chromosomes. Inhibition of telomerase activity leads the cells to senescence and death. Myelodysplastic syndromes (MSD) are hematological malignancies characterized by peripheral blood cytopenia and ineffective hematopoiesis. Telomerase activity and hTERT expression in MDS patients were independently investigated by different groups obtaining contradictory results. We analyzed telomerase activity and hTERT expression in the bone marrow of ten control, 15 MDS patients and two patients with AML, likely evolved from a previous MDS. Moreover, the expression of c-myc, mad1, p53 (transcription factors involved in hTERT expression regulation), has been investigated. Telomerase activity and hTERT expression increased in the MDS patients with respect to the controls. The analysis of the MDS subgroups, indicated that patients with more severe disease demonstrated significantly higher levels of hTERT expression and telomerase activity with respect to the patients with more favorable disease. c-Myc and p53 expressions were not significantly different between controls and MDS patients, whereas mad1 expression was increased in MDS patiens, particularly in those with more favorable disease. We hypothesize that mad1 increase can contribute to reduce the hTERT expression in the early stage of disease and we suggest that hTERT expression and telomerase activity, whether confirmed in larger series of cases could support other parameters in the diagnosis and stadiation of MDS

AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon Cancer Cells

PPARαs are nuclear receptors highly expressed in colon cells. They can be activated by the fibrates (clofibrate, ciprofibrate etc.) used to treat hyperlipidemia. Since PPARα transcriptional activity can be negatively regulated by JNK, the inhibition of JNK activity could increase the effectiveness of PPARα ligands. We analysed the effects of AS601245 (a JNK inhibitor) and clofibrate alone or in association, on proliferation, apoptosis, differentiation and the gene expression profile of CaCo-2 human colon cancer cells. Proliferation was inhibited in a dose-dependent way by clofibrate and AS601245. Combined treatment synergistically reduced cell proliferation, cyclin D1 and PCNA expression and induced apoptosis and differentiation. Reduction of cell proliferation, accompanied by the modulation of p21 expression was observed in HepG2 cells, also. Gene expression analysis revealed that some genes were highly modulated by the combined treatment and 28 genes containing PPRE were up-regulated, while clofibrate alone was ineffective. Moreover, STAT3 signalling was strongly reduced by combined treatment. After combined treatment, the binding of PPARα to PPRE increased and paralleled with the expression of the PPAR coactivator MED1. Results demonstrate that combined treatment increases the effectiveness of both compounds and suggest a positive interaction between PPARα ligands and anti-inflammatory agents in humans

EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro- apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.This research was funded by Roswell Park Cancer Institute’s Cancer Center Support Grant from National Cancer Institute, NIH P30CA016056 (RP) and a generous donation by Richard and Deidre Turner (RP). This investigation was conducted in-part in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 RR020128-01 from the National Center for Research Resources, National Institutes of Health

In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

SummaryCurrent treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1–4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease