Sphingosine kinase 1 in breast cancer: A new molecular marker and a therapy target

It is now well-established that sphingosine kinase 1 (SK1) plays a significant role in breast cancer development, progression, and spread, whereas SK1 knockdown can reverse these processes. In breast cancer cells and tumors, SK1 was shown to interact with various pathways involved in cell survival and chemoresistance, such as nuclear factor-kappa B (NFκB), Notch, Ras/MAPK, PKC, and PI3K. SK1 is upregulated by estrogen signaling, which, in turn, confers cancer cells with resistance to tamoxifen. Sphingosine-1-phosphate (S1P) produced by SK1 has been linked to tumor invasion and metastasis. Both SK1 and S1P are closely linked to inflammation and adipokine signaling in breast cancer. In human tumors, high SK1 expression has been linked with poorer survival and prognosis. SK1 is upregulated in triple negative tumors and basal-like subtypes. It is often associated with high phosphorylation levels of ERK1/2, SFK, LYN, AKT, and NFκB. Higher tumor SK1 mRNA levels were correlated with poor response to chemotherapy. This review summarizes the up-to-date evidence and discusses the therapeutic potential for the SK1 inhibition in breast cancer, with emphasis on the mechanisms of chemoresistance and combination with other therapies such as gefitinib or docetaxel. We have outlined four key areas for future development, including tumor microenvironment, combination therapies, and nanomedicine. We conclude that SK1 may have a potential as a target for precision medicine, its high expression being a negative prognostic marker in ER-negative breast cancer, as well as a target for chemosensitization therapy

Leptin signalling, obesity and prostate cancer: molecular and clinical perspective on the old dilemma

The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited. Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive. Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies

Bradycardia and syncope as sole manifestations of a cranial lesion:a case report

BACKGROUND: Bradycardia and syncope are known sequelae of brain lesions. However, in the absence of neurological signs and symptoms, bradycardia and syncope are often investigated purely from the cardiovascular perspective and central nervous system-related causes may be easily overlooked during differential diagnosis. CASE PRESENTATION: Here we report a case of a 69-year-old Caucasian man who presented to the emergency department after a fall. He had 1-year history of syncope and bradycardia with frequent ectopic beats shown on his electrocardiogram. He had no neurological symptoms. He was previously investigated as an out-patient and a diagnosis of idiopathic bradycardia with ventricular ectopic beats was made. On admission, cardiovascular investigations could not reveal the cause of his bradycardia. Computed tomography and magnetic resonance imaging scans of his head showed a localized mass in left basal ganglia consistent with infiltrating glioma. CONCLUSION: To the best of our knowledge this is the first case report demonstrating central nervous system-related bradycardia and syncope without other neurological symptoms. This case will serve as a useful reminder to general practitioners, accident and emergency doctors, and cardiologists

An unusual case of disseminated intravascular coagulation

The use of cardiac pacemakers is increasing worldwide. Infective endocarditis from a pacemaker lead is a rare, but one of the most severe complications of pacemaker insertion. The diagnosis of pacemaker-related infective endocarditis is usually delayed due to unspecific clinical signs and symptoms at presentation compared to native valve infective endocarditis. Several factors can increase the risk of cardiac pacemaker-related infective endocarditis including cachexia, malignancy, diabetes mellitus, immunosuppression and corticosteroid treatment. This case report is about a 70-year-old diabetic male who presented to the emergency department with disseminated intravascular coagulation (DIC), cardiac and liver failure. He was diagnosed with pacemaker infective endocarditis, which was ultimately fatal

Combination of RAD001 (everolimus) and docetaxel reduces prostate and breast cancer cell VEGF production and tumour vascularisation independently of sphingosine-kinase-1

Resistance to docetaxel is a key problem in current prostate and breast cancer management. We have recently discovered a new molecular mechanism of prostate cancer docetaxel chemoresistance mediated by the mammalian target of rapamycin (mTOR)/sphingosine-kinase-1 (SK1) pathway. Here we investigated the influence of this pathway on vascular endothelial growth factor (VEGF) production and tumour vascularisation in hormone resistant prostate and breast cancer models. Immunofluorescent staining of tumour sections from human oestrogen receptor (ER)-negative breast cancer patients showed a strong correlation between phosphorylated P70S6 kinase (mTOR downstream target), VEGF and SK1 protein expression. In hormone-insensitive prostate (PC3) and breast (MDA-MB-231 and BT-549) cancer cell lines the mTOR inhibitor RAD001 (everolimus) has significantly inhibited SK1 and VEGF expression, while low dose (5 nM) docetaxel had no significant effect. In these cell lines, SK1 overexpression slightly increased the basal levels of VEGF, but did not block the inhibitory effect of RAD001 on VEGF. In a human prostate xenograft model established in nude mice, RAD001 alone or in combination with docetaxel has suppressed tumour growth, VEGF expression and decreased tumour vasculature. Overall, our data demonstrate a new mechanism of an independent regulation of SK1 and VEGF by mTOR in hormone-insensitive prostate and breast cancers

Core shell lipid-polymer hybrid nanoparticles with combined docetaxel and molecular targeted therapy for the treatment of metastatic prostate cancer

Many prostate cancers relapse after initial chemotherapy treatment. Combining molecular and chemotherapy together with encapsulation of drugs in nanocarriers provides effective drug delivery and toxicity reduction. We developed core shell lipid-polymer hybrid nanoparticles (CSLPHNPs) with poly (lactic-co-glycolic acid) (PLGA) core and lipid layer containing docetaxel and clinically used inhibitor of sphingosine kinase 1 (SK1) FTY720 (fingolimod). We show for the first time that FTY720 (both free and in CSLPHNPs) re-sensitizes castrate resistant prostate cancer cells and tumors to docetaxel, allowing a four-fold reduction in effective dose. Our CSLPHNPs showed high serum stability and a long shelf life. CSLPHNPs demonstrated a steady uptake by tumor cells, sustained intracellular drug release and in vitro efficacy superior to free therapies. In a mouse model of human prostate cancer, CSLPHNPs showed excellent tumor targeting and significantly lower side effects compared to free drugs, importantly, reversing lymphopenia induced by FTY720. Overall, we demonstrate that nanoparticle encapsulation can improve targeting, provide low off-target toxicity and most importantly reduce FTY720-induced lymphopenia, suggesting its potential use in clinical cancer treatment

Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting

Sphingosine kinases 1 and 2 (SK1 and SK2) are proto-oncogenic isozymes expressed in many human tumors and associated with chemoresistance and poor prognosis. They are well-recognized therapy targets and their inhibition was shown to induce tumor volume reduction and chemosensitization in multiple cancer models. Oncogenic signaling is extremely complex and often cross-regulated. Designing molecular therapies and their combinations requires rational approaches to avoid redundant targeting or developing resistance. In this study, we have performed RNA transcriptome microarray analysis of two breast and two prostate metastatic cancer cell lines treated with siRNAs targeting SK1 or SK2. In prostate cancer cell lines SK1 knockdown (KD) has significantly changed expression of several genes including downregulation of NSUN2, G3BP2 and upregulation of ETS1. SK2 KD also affected expression of multiple genes including downregulation of CAPZA1 NSUN3 and ADPGK and upregulation of VDAC1, IBTK, ETS1, and MKNK2. Similarly, in breast cancer cells SK1 KD led to downregulation of NSUN2, NFATC3, CDK2, and G3BP2 and upregulation of GTF2B, TTC17, and RAB23. SK2 KD in breast cancer cells has decreased expression of ITGAV and CAPZA1 and increased expression of GTF2B and ST13. Gene-set enrichment analysis of known biochemical pathways showed that in prostate and breast cell lines SKs KD have altered multiple pathways. SK1 KD altered chromatin assembly, regulation of G1/S transition and mitosis, Wnt and MAP kinase signaling and cell motility. SK2 KD altered RAS protein signal transduction, regulation of MAP kinase and serine/threonine kinase activity, cell motility, small GTPase mediated signal transduction and phosphatidylinositol 3-kinase (PI3K) signaling. Through genome-wide microarray analysis, we have identified important molecular pathways affected by SK1 and SK2 KD. It appears that while KD of both genes leads to a decrease in individual pro-tumorigenic genes, there is a universal cellular response resulting in upregulation of several known pro-survival and pro-tumorigenic pathways such as MAPK, RAS, and PI3K, which may mediate cancer resistance to anti-SKs therapies. Our data point out to the potential advantage of certain molecular therapy combinations in targeting prostate and breast cancer. Further signaling studies are required to confirm the individual involvement of identified pathways

Everolimus (RAD001) sensitizes prostate cancer cells to docetaxel by down-regulation of HIF-1α and sphingosine kinase 1

Resistance to docetaxel is a key problem in current prostate cancer management. Sphingosine kinase 1 (SK1) and phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways have been implicated in prostate cancer chemoresistance. Here we investigated whether their combined targeting may re-sensitize prostate cancer cells to docetaxel. In hormone-insensitive PC-3 and DU145 prostate cancer cells the mTOR inhibitor everolimus (RAD001) alone did not lead to significant cell death, however, it strongly sensitized cells to low levels (5 nM) of docetaxel. We show that mTOR inhibition has led to a decrease in hypoxia-inducible factor-1α (HIF-1α) protein levels and SK1 mRNA. HIF-1α accumulation induced by CoCl2 has led to a partial chemoresistance to RAD001/docetaxel combination. SK1 overexpression has completely protected prostate cancer cells from RAD001/docetaxel effects. Using gene knockdown and CoCl2 treatment we showed that SK1 mRNA expression is downstream of HIF-1α. In a human xenograft model in nude mice single RAD001 and docetaxel therapies induced 23% and 15% reduction in prostate tumor volume, respectively, while their combination led to a 58% reduction. RAD001 alone or in combination with docetaxel has suppressed intratumoral mTOR and SK1 signaling, however as evidenced by tumor size, it required docetaxel for clinical efficacy. Combination therapy was well tolerated and had similar levels of toxicity to docetaxel alone. Overall, our data demonstrate a new mechanism of docetaxel sensitization in prostate cancer. This provides a mechanistic basis for further clinical application of RAD001/docetaxel combination in prostate cancer therapy

On the survival of individuals diagnosed with type 2 diabetes mellitus in the United Kingdom:A retrospective matched cohort study

Aims: To estimate long-term hazards of all-cause mortality following a diagnosis of type 2 diabetes mellitus (T2DM) using electronic primary care data. Methods: Retrospective matched cohort study using electronic health records from THIN primary care database. Individuals born between 1930 and 1960, diagnosed with T2DM between 2000 and 2016 and aged 50–74 years were selected and followed up to 1 January 2017. Individuals with pre-existing selected severe medical conditions were excluded. The Gompertz-double-Cox model was used to estimate all-cause mortality hazards, adjusting for medical history, socio-demographic and lifestyle factors. Results: A total of 221 182 (57.6% Males, 30.8% T2DM) individuals were selected for the study of whom 29 618 (13.4%) died during follow-up. The adjusted mortality hazard of type 2 diabetes mellitus (T2DM) was estimated to be 1.21[1.12–1.3] and 1.52[1.44–1.6] among individuals diagnosed at 50–59 years and 60–74 years, respectively, compared to controls. Compared to the 1930–39 birth cohort, all-cause mortality hazards were reduced in the 1940–49 cohort, but increased at older ages in the 1950–60 birth cohort for both cases and controls. Conclusion: These hazards associated with T2DM which increase with age at diagnosis are constant across all birth cohorts demonstrating a lack of progress over time in reducing the relative risks of all-cause mortality associated with T2DM. A further study that includes people born after 1960 is needed to fully understand the emerging higher mortality hazards among the younger birth cohorts

A case of severe dry eye disease with corneal melting as presenting complaint of acute myeloid leukaemia

Dry eye syndrome is a common multifactorial disorder of the tear film and ocular surface. In rare cases, it may be caused by systemic diseases. Corneal melting is a complication of dry eye syndrome and is a potentially blinding condition. Here we report a case of a 67-year-old patient who attended her general practitioner for a year complaining of persistent dry eyes. Ophthalmological assessment showed severe dry eye syndrome with cornea melting in left eye. Blood test revealed anaemia and thrombocytopenia with circulating blasts. Bone marrow biopsy showed 15% myeloblasts with monosomy 7, compatible with acute myeloid leukaemia. Patient was started on intensive chemotherapy regime and was a candidate for allogenic bone marrow transplant. To our knowledge, this is the first case report demonstrating dry eye syndrome with sterile corneal melting as the possible presenting complaints of acute myeloid leukaemia. This case will serve as a useful reminder to general practitioners and accident and emergency doctors about the current guidelines regarding referral of persistently symptomatic patients with dry eye syndrome for further investigation in secondary care