Display omitted
The link between prostate cancer (PC) development and lipid metabolism is well established, with AR intimately involved in a number of lipogenic processes involving SREBP1, PPARG, ...FASN, ACC, ACLY and SCD1. Recently, there is growing evidence implicating the role of obesity and peri-prostatic adipose tissue (PPAT) in PC aggressiveness and related mortality, suggesting the importance of lipid pathways in both localised and disseminated disease. A number of promising agents are in development to target the lipogenic axis in PC, and the likelihood is that these agents will form part of combination drug strategies, with targeting of multiple metabolic pathways (e.g. FASN and CPT1), or in combination with AR pathway inhibitors (SCD1 and AR).
Mechanisms of FGFR-mediated carcinogenesis Ahmad, Imran; Iwata, Tomoko; Leung, Hing Y.
Biochimica et biophysica acta,
April 2012, 2012-Apr, 2012-04-00, Letnik:
1823, Številka:
4
Journal Article
Recenzirano
Odprti dostop
In this review, the evidence for a role of fibroblast growth factor receptor (FGFR) mediated signalling in carcinogenesis are considered and relevant underlying mechanisms highlighted. FGF signalling ...mediated by FGFR follows a classic receptor tyrosine kinase signalling pathway and its deregulation at various points of its cascade could result in malignancy. Here we review the accumulating reports that revealed the association of FGF/FGFRs to various types of cancer at a genetic level, along with in vitro and in vivo evidences available so far, which indicates the functional involvement of FGF signalling in tumour formation and progression. An increasing number of drugs against the FGF pathways is currently in clinical testing. We will discuss the strategies for future FGF research in cancer and translational approaches.
► Role for FGFR mediated signalling in cancer. ► FGFR as a target of therapy. ► Future perspectives.
Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation of AR signalling remains the main driver of castration-resistant prostate cancer (CRPC) progression. In this ...study, we perform a comprehensive unbiased characterisation of LNCaP cells chronically exposed to multiple AR inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant cells and associated with perturbed glucose and lipid metabolism. To exploit this phenotype, we delineate a subset of proteins consistently associated with ARI resistance and highlight mitochondrial 2,4-dienoyl-CoA reductase (DECR1), an auxiliary enzyme of beta-oxidation, as a clinically relevant biomarker for CRPC. Mechanistically, DECR1 participates in redox homeostasis by controlling the balance between saturated and unsaturated phospholipids. DECR1 knockout induces ER stress and sensitises CRPC cells to ferroptosis. In vivo, DECR1 deletion impairs lipid metabolism and reduces CRPC tumour growth, emphasizing the importance of DECR1 in the development of treatment resistance.
Cell death is a natural process in organismal development, homeostasis and response to disease or infection that eliminates unnecessary or potentially dangerous cells and acts as an innate barrier to ...oncogenesis. Inactivation of cell death is a key step in tumour development and also impedes effective response to cancer therapy. Precise execution of unwanted cells is achieved through regulated cell death processes including the intrinsic apoptotic pathway that is governed by the BCL-2 (B-cell lymphoma 2) protein family. There is compelling evidence that intrinsic apoptosis is defective in prostate cancer, particularly in metastatic and castration resistant advanced disease, currently a lethal diagnosis. New therapeutics have been developed to target pro-survival BCL-2 proteins (including BCL-2, BCL-XL and MCL-1) and show promise in reinstating apoptosis to destroy tumour cells in haematological cancers. Here we discuss perturbation of cell death in prostate cancer and how new therapeutics could improve treatment outcome in prostate cancer.
•There has been little progress in development of new therapies capable of substantial survival improvement in advanced prostate cancer.•Perturbation of apoptotic pathways contributes to prostate cancer development, progression and resistance to therapy.•Pharmaceutically reinstating intrinsic apoptosis can dramatically improve survival in some haematopoietic cancers.•Evidence is emerging that these BH3-mimetic drugs may be efficacious in prostate cancer when used as combination therapies.
Peroxisome Proliferator-Activated Receptor Gamma (PPARG) is one of the three members of the PPAR family of transcription factors. Besides its roles in adipocyte differentiation and lipid metabolism, ...we recently demonstrated an association between PPARG and metastasis in prostate cancer. In this study a functional effect of PPARG on AKT serine/threonine kinase 3 (AKT3), which ultimately results in a more aggressive disease phenotype was identified. AKT3 has previously been shown to regulate PPARG co-activator 1 alpha (PGC1α) localisation and function through its action on chromosome maintenance region 1 (CRM1). AKT3 promotes PGC1α localisation to the nucleus through its inhibitory effects on CRM1, a known nuclear export protein. Collectively our results demonstrate how PPARG over-expression drives an increase in AKT3 levels, which in turn has the downstream effect of increasing PGC1α localisation within the nucleus, driving mitochondrial biogenesis. Furthermore, this increase in mitochondrial mass provides higher energetic output in the form of elevated ATP levels which may fuel the progression of the tumour cell through epithelial to mesenchymal transition (EMT) and ultimately metastasis.
Members of epidermal growth factor receptor (EGFR) or ErbB receptor family play a critical role in a wide range of human cancers. In the past decade, there has been a remarkable progress in ...developing ErbB targeted therapeutics. However, a substantial portion of patients has non-responsive disease or subsequently shows evidence of tumour relapse following initial success with anti-ErbB agents. Improved insights into the biology of ErbB receptor family have led to more effective second- and third-generation anti-ErbB therapies. In this review, we have summarised salient features of the ErbB receptor physiology and highlighted key mechanisms involved in abnormal ErbB signalling in tumorigenesis. The rationale of anti-ErbB receptor therapies are outlined along with key mechanisms proposed for resistance to treatment as well as the current concept of combined anti-ErbB therapies. In conclusion, improved understanding of the molecular pathways that confer resistance to anti-ErbB therapeutics will be essential in minimising tumour resistance to ErbB targeted treatments.
Human exhibit wide variations in their metabolic profiles because of differences in genetic factors, diet and lifestyle. Therefore in order to detect metabolic differences between individuals robust ...analytical methods are required. A protocol was produced based on the use of Liquid Chromatography- High Resolution Mass Spectrometry (LC-HRMS) in combination with orthogonal Hydrophilic Interaction (HILIC) and Reversed Phase (RP) liquid chromatography methods for the analysis of the urinary metabolome, which was then evaluated as a diagnostic tool for prostate cancer (a common but highly heterogeneous condition). The LC-HRMS method was found to be robust and exhibited excellent repeatability for retention times (<±1%), and mass accuracy (<±1 ppm). Based on normalised data (against creatinine levels, osmolality or MS total useful signals/MSTUS) coupled with supervised multivariate analysis using Orthogonal Partial Least Square-Discriminant Analysis (OPLS-DA), we were able to discriminate urine samples from men with or without prostate cancer with R2Y(cum) >0.9. In addition, using the receiver operator characteristics (ROC) test, the area under curve (AUC) for the combination of the four best characterised biomarker compounds was 0.896. The four biomarker compounds were also found to differ significantly (P<0.05) between an independent patient cohort and controls. This is the first time such a rigorous test has been applied to this type of model. If validated, the established protocol provides a robust approach with a potentially wide application to metabolite profiling of human biofluids in health and disease.
Optical techniques are widely used tools in the visualisation of biological species within complex matrices, including biopsies, tissue resections and biofluids. Raman spectroscopy is an emerging ...analytical approach that probes the molecular signature of endogenous cellular biomolecules under biocompatible conditions with high spatial resolution. Applications of Raman spectroscopy in prostate cancer include biopsy analysis, assessment of surgical margins and monitoring of treatment efficacy. The advent of advanced Raman imaging techniques, such as stimulated Raman scattering, is creating opportunities for real-time in situ evaluation of prostate cancer. This review provides a focus on the recent preclinical and clinical achievements in implementing Raman-based techniques, highlighting remaining challenges for clinical applications. The research and clinical results achieved through in vivo and ex vivo Raman spectroscopy illustrate areas where these evolving technologies can be best translated into clinical practice.
Combination therapy involving chemotherapeutic drugs and genes is emerging as a promising strategy to provide a synergistic therapeutic effect, to overcome drug resistance while reducing the severe ...side effects associated with conventional chemotherapeutic drugs. However, the lack of nanomedicines able to simultaneously carry anti-cancer drugs and nucleic acids limits the application of this therapeutic strategy. To overcome this issue, we proposed to synthesize a pro-drug dendrimer by conjugating the PEGylated, positively charged generation 3-diaminobutyric polypropylenimine dendrimer to the anti-cancer drug camptothecin with a redox-sensitive disulphide linkage, and evaluate its efficacy to co-deliver the complexed DNA and camptothecin to cancer cells. This PEGylated pro-drug dendrimer was found to spontaneously self-assemble into cationic (∼3-5 mV) vesicles at pH 7.4, at a critical aggregation concentration of about 200 μg mL
. These vesicles (dendrimersomes) became smaller (150-200 nm) with increasing dendrimer concentration and remained stable over 7 days. They were able to release about 70% of the conjugated camptothecin in presence of 50 mM glutathione (equivalent to the intracellular environment of tumor tissue). They could also condense more than 85% of the DNA at dendrimer : DNA weight ratios of 5 : 1 and higher. DNA condensation occurred instantly and was found to be stable for at least 24 h. This led to an enhanced cellular uptake of DNA (by up to 1.6-fold) and increased gene transfection (by up to 2.4-fold) in prostate cancer cells in comparison with the unmodified dendrimer. These novel dendrimersomes are therefore promising for single carrier-based combination cancer therapy.
PDF
