Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review.
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ABSTRACT:
SUBMITTER: Ferrari E
PROVIDER: S-EPMC8196904 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Progression from early forms of prostate cancer to castration-resistant disease is associated with an increase in signal transduction activity. The majority of castration-resistance cancers persist in the expression of the androgen receptor (AR), as well as androgen-dependent genes. The AR is regulated not only by it associated steroid hormone, but also by manifold regulatory and signaling molecules, including several kinases. We undertook evaluation of the role of Lemur Tyrosine Kinase 2 (LMTK2) in modulating AR activity, as several Genome Wide Association Studies (GWAS) have shown a marked association of LMTK2 activity with the development of prostate cancer. We confirm that not only is LMTK2 mRNA reduced in prostate cancer tissue, but also LMTK2 protein levels are markedly diminished. Knockdown of LMTK2 protein in prostate cell lines greatly increased the transcription of androgen-responsive genes. In addition, LMTK2 knockdown led to an increase in prostate cancer stem cell populations in LNCaP cells, indicative of increased tumorogenicity. Using multiple approaches, we also demonstrate that LMTK2 interacts with the AR, thus putting LMTK2 as a component of a signaling complex modulating AR activity. Our finding that LMTK2 is a negative regulator of AR activity defines a novel cellular pathway for activation of AR-responsive genes in castrate resistant-prostate cancer. Moreover, pharmacologic manipulation of LMTK2 activity will provide a novel therapeutic target for more effective treatments for patients with castrate-resistant prostate cancer.
| S-EPMC4546463 | biostudies-literature
Project description:Prostate cancer responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here, we demonstrate that BMX expression in prostate cancer is suppressed directly by AR via binding to the BMX gene and that BMX expression is subsequently rapidly increased in response to ADT. BMX contributed to CRPC development in cell line and xenograft models by positively regulating the activities of multiple receptor tyrosine kinases through phosphorylation of a phosphotyrosine-tyrosine (pYY) motif in their activation loop, generating pYpY that is required for full kinase activity. To assess BMX activity in vivo, we generated a BMX substrate-specific antibody (anti-pYpY) and found that its reactivity correlated with BMX expression in clinical samples, supporting pYY as an in vivo substrate. Inhibition of BMX with ibrutinib (developed as an inhibitor of the related Tec kinase BTK) or another BMX inhibitor BMX-IN-1 markedly enhanced the response to castration in a prostate cancer xenograft model. These data indicate that increased BMX in response to ADT contributes to enhanced tyrosine kinase signaling and the subsequent emergence of CRPC, and that combination therapies targeting AR and BMX may be effective in a subset of patients.Significance: The tyrosine kinase BMX is negatively regulated by androgen and contributes to castration-resistant prostate cancer by enhancing the phosphorylation and activation of multiple receptor tyrosine kinases following ADT. Cancer Res; 78(18); 5203-15. ©2018 AACR.
| S-EPMC6139052 | biostudies-literature
Project description:Large-scale transcriptome and methylome data analyses obtained by high-throughput technologies have been enabling the identification of novel imprinted genes. We investigated genome-wide DNA methylation patterns in multiple human tissues, using a high-resolution microarray to uncover hemimethylated CpGs located in promoters overlapping CpG islands, aiming to identify novel candidate imprinted genes. Using our approach, we recovered ~30% of the known human imprinted genes, further 168 candidates were identified, 61 of which with at least three hemimethylated CpGs shared by more than two tissue types. Thirty-four of these candidate genes are members of the protocadherins cluster on 5q31.3; in mice, protocadherin genes have non-imprinted monoallelic randomic expression, which might be the case in humans. Among the remaining 27 genes, ZNF331 was recently validated as an imprinted gene, and six of them have been reported as candidates, supporting our prediction. Five candidates (CCDC166, ARC, PLEC, TONSL and VPS28) map to 8q24.3, and might constitute a novel imprinted cluster. Additionally, we performed a comprehensive compilation of known human and mice imprinted genes from literature and databases, and a comparison among high-throughput imprinting studies in humans. The screening for hemimethylated CpGs shared by multiple human tissues, together with the extensive review, appears as a useful approach to reveal candidate imprinted genes.
2017-09-26 | GSE103413 | GEO
Project description:The Abelson (c-Abl) proto-oncogene encodes a highly conserved nonreceptor protein tyrosine kinase that plays a role in cell proliferation, differentiation, apoptosis and cell adhesion. c-Abl represents a specific anti-cancer target in prostate cancer as aberrant activity of this kinase has been implicated in the stimulation of prostate cancer growth and progression. However, the mechanism of regulation of c-Abl is not known. Here we report that Abl kinases are regulated by a novel microRNA, miR-4723, in prostate cancer. Expression profiling of miR-4723 expression in a cohort of prostate cancer clinical specimens showed that miR-4723 expression is widely attenuated in prostate cancer. Low miR-4723 expression was significantly correlated with poor survival outcome and our analyses suggest that miR-4723 has significant potential as a disease biomarker for diagnosis and prognosis in prostate cancer. To evaluate the functional significance of decreased miR-4723 expression in prostate cancer, miR-4723 was overexpressed in prostate cancer cell lines followed by functional assays. miR-4723 overexpression led to significant decreases in cell growth, clonability, invasion and migration. Importantly, miR-4723 expression led to dramatic induction of apoptosis in prostate cancer cell lines suggesting that miR-4723 is a pro-apoptotic miRNA regulating prostate carcinogenesis. Analysis of putative miR-4723 targets showed that miR-4723 targets integrin alpha 3 and Methyl CpG binding protein in addition to Abl1 and Abl2 kinases. Further, we found that the expression of Abl kinase is inversely correlated with miR-4723 expression in prostate cancer clinical specimens. Also, Abl1 knockdown partially phenocopies miR-4723 reexpression in prostate cancer cells suggesting that Abl is a functionally relevant target of miR-4723 in prostate cancer. In conclusion, we have identified a novel microRNA that mediates regulation of Abl kinases in prostate cancer. This study suggests that miR-4723 may be an attractive target for therapeutic intervention in prostate cancer.
| S-EPMC3815229 | biostudies-literature
Project description:ContextCancer and its treatments cause fatigue in up to 90% of men with advanced prostate cancer. As men with prostate cancer are surviving longer, cancer-related fatigue is becoming increasingly important for clinicians to understand and proactively manage.ObjectiveThe aim of this work is to identify knowledge gaps that may support healthcare professionals to recommend personalised fatigue management strategies.Evidence acquisitionThis manuscript is based on a roundtable discussion held during the European Association of Urology 2022 Annual Symposium, combined with a review of the literature. Five core themes were generated from the roundtable: (1) meaning of fatigue in prostate cancer patients, (2) impact of fatigue, (3) association between fatigue and treatment selection, (4) benefits of managing fatigue, and (5) barriers to exercise.Evidence synthesisCancer-related fatigue has complex underlying aetiology and is a subjective experience that may be under-reported. Some studies have shown that techniques such as education, cognitive behavioural therapy, guided imagery, and progressive muscle relaxation can result in clinically meaningful improvements in fatigue. However, the largest body of evidence, and a theme echoed in the roundtable discussions, was the benefit of exercise on fatigue. Despite the benefits of exercise, for some men, objective barriers to exercise exist and knowledge of benefits does not automatically translate into implementation and adherence.ConclusionsUnderstanding the specific health needs of individual patients and their desired health outcomes is essential to identify personalised strategies for minimising fatigue. As an outcome of the roundtable meeting, we developed a quick reference guide for healthcare providers. A high-resolution copy can be downloaded from https://patients.uroweb.org/library/fatigue-in-prostate-cancer-patients-guide/.Patient summaryThis article is based on dialogue between a group of specialists, patients, and caregivers, which took place at a roundtable meeting during the European Association of Urology 2022 Annual Symposium. The group discussed how healthcare providers can best support their patients who experience fatigue. The group subsequently developed a guide to help healthcare providers during appointments.
| S-EPMC11001642 | biostudies-literature
Project description:The PI3K/AKT pathway is hyperactivated in prostate cancer but its effective therapeutic targeting has proven difficult. In particular, the antitumor activity of AKT inhibitors is attenuated by upregulation of receptor tyrosine kinases (RTK) through an uncharacterized feedback mechanism. In this report, we show that RNA interference-mediated silencing or pharmacologic inhibition of Pim-1 activity curtails AKT inhibitor-induced upregulation of RTKs in prostate cancer cells. Although Pim kinases have been implicated in cap-dependent translational control, we find that in the context of AKT inhibition, the expression of RTKs is controlled by Pim-1 in a cap-independent manner by controlling internal ribosome entry. Combination of Pim and AKT inhibitors resulted in synergistic inhibition of prostate tumor growth in vitro and in vivo. Together, our results show that Pim-1 mediates resistance to AKT inhibition and suggest its targeting to improve the efficacy of AKT inhibitors in anticancer therapy.
| S-EPMC3680595 | biostudies-literature
Project description:Lemur Tyrosine Kinase 2 (LMTK2) is a recently cloned transmembrane protein, actually a serine/threonine kinase named after the Madagascar primate lemur due to the long intracellular C-terminal tail. LMTK2 is relatively little known, compared to other kinases but its role has been increasingly recognized. Published data show that LMTK2 regulates key cellular events, including endocytic trafficking, nerve growth factor signaling, apoptosis, and Cl- transport. Abnormalities in the expression and function of LMTK2 are associated with human disease, such as neurodegeneration, cancer and infertility. We summarized the current state of knowledge on LMTK2 structure, regulation, interactome, intracellular localization, and tissue expression and point out future research directions to better understand the role of LMTK2.
| S-EPMC6361741 | biostudies-other
Project description:ObjectiveProstate cancer (PCA) is the most common malignancy and a major cause of death in men but, importantly, a substantial proportion will live for several years following diagnosis. However, they face the prospect of experiencing symptoms, side-effects of treatment and diminished quality of life. The patient's psychological adjustment is particularly complex, given the potential trajectory of the disease, from the point of diagnosis, with its immediate impact, to the phase of palliative care, with its attendant issue of facing mortality. Since a comprehensive review of the literature on psychological adjustment of men with PCA has not yet been done, we have documented relevant research, integrated findings and drawn conclusions, where possible, in order to map out clinical and research implications.MethodWe searched 5 databases for the period 1994 - July 2006, during which most of the work in the field has been done.ResultsWe found few studies of substance among the 60 we examined to draw conclusions about psychological adjustment to prostate cancer and its treatment. This is in marked contrast to the picture in breast cancer. While some patterns have emerged, many gaps remain to be filled.DiscussionAspects of methodology need attention, particularly longitudinal, prospective designs, incorporation of control groups and the use of valid and reliable measures. There is scope for qualitative studies as a complement to quantitative research.
| S-EPMC1805773 | biostudies-literature
Project description:Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials. One group of representative targeted oncogenic kinases, the receptor tyrosine kinases (RTKs), has been associated with gastric cancer development. Trastuzumab, an inhibitor of ERBB2, has been approved for the treatment of gastric cancer, although other receptor tyrosine kinases, such as epidermal growth factor receptor, vascular endothelial growth factor, platelet-derived growth factor receptor, c-Met, IGF-1R and fibroblast growth factor receptor 2, are also activated in gastric cancer. The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients. On the other hand, the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients; however, a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial. Other clinical trials, especially phase III trials that have tested drugs targeting RTKs, such as cetuximab, panitumumab, gefitinib, erlotinib, figitumumab, sorafenib, sunitinib and lapatinib, have shown that these drugs have modest effects against gastric cancer. This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.
| S-EPMC4000490 | biostudies-other
Project description:ObjectiveTo review studies of patients' and carers' experience of prostate cancer care.DesignNarrative literature review.MethodsSearch strategies were developed for the following databases: MEDLINE (1966-2006), EMBASE (1980-2006), CINAHL (1982-2006) and PsycINFO (1987-2006). A search of SIGLE (System for Information on Grey Literature in Europe) was also undertaken. Experience was defined as patients' and carers' reports of how care was organized and delivered to meet their needs. A narrative summary of the included papers was undertaken.ResultsA total of 90 relevant studies were identified. Most studies reported on experiences of screening, diagnosis, the treatment decision, treatment and post-initial treatment. Few studies reported on experiences of the stages of referral, testing, and further treatment and palliative care, and no studies reported on monitoring or terminal care.ConclusionsAlthough some phases of care have not been investigated in detail, there is evidence that: (i) many patients have a low level of knowledge of prostate cancer; (ii) patients with prostate cancer and their carers need information throughout the care pathway to enable them to understand the diagnosis, treatment options, self-care and support available; and (iii) increasing patient knowledge and understanding of prostate cancer (e.g. through interventions) are often associated with a more active role in decision making (e.g. screening, treatment decision).
| S-EPMC5060497 | biostudies-literature