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Sphingosine Kinase Activity Is Not Required for Tumor Cell Viability  [PDF]
Karen Rex, Shawn Jeffries, Matthew L. Brown, Timothy Carlson, Angela Coxon, Flordeliza Fajardo, Brendon Frank, Darin Gustin, Alexander Kamb, Paul D. Kassner, Shyun Li, Yihong Li, Kurt Morgenstern, Matthew Plant, Kim Quon, Astrid Ruefli-Brasse, Joanna Schmidt, Elissa Swearingen, Nigel Walker, Zhulun Wang, J. E. Vivienne Watson, Dineli Wickramasinghe, Mariwil Wong, Guifen Xu, Holger Wesche
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068328
Abstract: Sphingosine kinases (SPHKs) are enzymes that phosphorylate the lipid sphingosine, leading to the formation of sphingosine-1-phosphate (S1P). In addition to the well established role of extracellular S1P as a mitogen and potent chemoattractant, SPHK activity has been postulated to be an important intracellular regulator of apoptosis. According to the proposed rheostat theory, SPHK activity shifts the intracellular balance from the pro-apoptotic sphingolipids ceramide and sphingosine to the mitogenic S1P, thereby determining the susceptibility of a cell to apoptotic stress. Despite numerous publications with supporting evidence, a clear experimental confirmation of the impact of this mechanism on tumor cell viability in vitro and in vivo has been hampered by the lack of suitable tool reagents. Utilizing a structure based design approach, we developed potent and specific SPHK1/2 inhibitors. These compounds completely inhibited intracellular S1P production in human cells and attenuated vascular permeability in mice, but did not lead to reduced tumor cell growth in vitro or in vivo. In addition, siRNA experiments targeting either SPHK1 or SPHK2 in a large panel of cell lines failed to demonstrate any statistically significant effects on cell viability. These results show that the SPHK rheostat does not play a major role in tumor cell viability, and that SPHKs might not be attractive targets for pharmacological intervention in the area of oncology.
Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation  [PDF]
Volkert A. L. Huurman, Robert Hilbrands, Gabri?lle G. M. Pinkse, Pieter Gillard, Gaby Duinkerken, Pieter van de Linde, Petronella M. W. van der Meer-Prins, Minke F. J. Versteeg-van der Voort Maarschalk, Koen Verbeeck, Behrooz Z. Alizadeh, Chantal Mathieu, Frans K. Gorus, Dave L. Roelen, Frans H. J. Claas, Bart Keymeulen, Daniel G. Pipeleers, Bart O. Roep
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002435
Abstract: Background Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin–independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function. Methodology/Principal Findings Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters - including time until insulin independence, insulin independence at one year, and C-peptide levels over one year- remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome. Conclusions/Significance In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression. Trial Registration Clinicaltrials.gov NCT00623610
Regulation of cancer cell migration and invasion by sphingosine-1-phosphate  [cached]
James R Van Brocklyn
World Journal of Biological Chemistry , 2010,
Abstract: Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that has been implicated in regulation of a number of cancer cell malignant behaviors, including cell proliferation, survival, chemotherapeutic resistance and angiogenesis. However, the effects of S1P on cancer cell migration, invasion and metastasis, are perhaps its most complex, due to the fact that, depending upon the S1P receptors that mediate its responses and the crosstalk with other signaling pathways, S1P can either positively or negatively regulate invasion. This review summarizes the effects of S1P on cancer cell invasion and the mechanisms by which it affects this important aspect of cancer cell behavior.
Expressions of Sphingosine-1-phosphate (S1P) Receptors, Sphingosine Kinases in Malignant Bone and Soft Tissue Tumors, and The role of Sphingosine Kinase-1 in Growth of MFH Cell Lines  [PDF]
Shin-ichiro Kishimoto, Toshihiro Akisue, Kenta Kishimoto, Hitomi Hara, Masaya Imabori, Yoshiyuki Okada, Naomasa Fukase, Teruya Kawamoto, Ikuo Fujita, Takuya Fujimoto, Masahiro Kurosaka
Journal of Cancer Therapy (JCT) , 2011, DOI: 10.4236/jct.2011.22038
Abstract: Sphingolipids are ubiquitous components of cell membranes. Their metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) have important physiological functions, including regulation of cell growth and survival. S1P is generated by phosphorylation of sphingosine catalyzed by sphingosine kinase-1 (SPHK1). The purpose of this study is to explore the roles of S1P, S1P receptors, and sphingosine kinases in malignant musculoskeletal tumors. Twenty-one tumor samples (7 liposarcomas, 3 chondrosarcomas, 6 osteosarcomas, 5 MFH) obtained at open biopsy, and four human MFH cell lines (Nara H, Nara F, TNMY1, GBS-1) were used. We examined the mRNA expression of S1P receptors by RT-PCR, and the expression levels of SPHK by Real-time PCR. We used 4 MFH cell lines to analyze SPHK1 proteins by Western blotting. SPHK1 siRNA was transfected into MFH cell lines by lipofection method. Cell proliferation (control and transfected with siRNA) was assayed using WST-8 (Cell Counting Kit-8) assay. All high grade malignant tumors expressed S1P1, S1P2, S1P3 receptors, whereas the expression of S1P1 receptor was detected in 50% of low-grade malignant tumors, S1P2 receptor in 30%, and S1P3 in 50%. No statistically significant difference was found in the expression level of SPHK1 between high-grade and low-grade malignant tumors by Real-time PCR. By results of Western blotting, proteins of SPHK1 were expressed in all MFH cell lines. In MFH cell lines, transfection with SPHK1 siRNA oligonucleotides resulted in approximately 50 to 80% suppression of SPHK1 mRNA expression as determined by real-time PCR. Down-regulation of SPHK1 with small interfering RNA significantly reduced SPHK1 protein levels by Western blotting. Knock down of SPHK1 expression significantly decreased cell proliferation of all MFH cells. These results suggest that the expression of S1P receptors may play an important role for cell proliferation and may correlate with histologic grade in malignant bone and soft tissue tumors, and that SPHK1 may be one of essential molecules for cell proliferation in MFH cell lines.
Sphingosine Kinase 1 Is Required for Mesothelioma Cell Proliferation: Role of Histone Acetylation  [PDF]
Satish Kalari, Nagabhushan Moolky, Srikanth Pendyala, Evgeny V. Berdyshev, Cleo Rolle, Rajani Kanteti, Archana Kanteti, Wenli Ma, Donghong He, Aliya N. Husain, Hedy L. Kindler, Prasad Kanteti, Ravi Salgia, Viswanathan Natarajan
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045330
Abstract: Background Malignant pleural mesothelioma (MPM) is a devastating disease with an overall poor prognosis. Despite the recent advances in targeted molecular therapies, there is a clear and urgent need for the identification of novel mesothelioma targets for the development of highly efficacious therapeutics. Methodology/Principal Findings In this study, we report that the expression of Sphingosine Kinase 1 (SphK1) protein was preferentially elevated in MPM tumor tissues (49 epithelioid and 13 sarcomatoid) compared to normal tissue (n = 13). In addition, we also observed significantly elevated levels of SphK1 and SphK2 mRNA and SphK1 protein expression in MPM cell lines such as H2691, H513 and H2461 compared to the non-malignant mesothelial Met5 cells. The underlying mechanism appears to be mediated by SphK1 induced upregulation of select gene transcription programs such as that of CBP/p300 and PCAF, two histone acetyl transferases (HAT), and the down regulation of cell cycle dependent kinase inhibitor genes such as p27Kip1 and p21Cip1. In addition, using immunoprecipitates of anti-acetylated histone antibody from SphK inhibitor, SphK-I2 treated Met5A and H2691 cell lysates, we also showed activation of other cell proliferation related genes, such as Top2A (DNA replication), AKB (chromosome remodeling and mitotic spindle formation), and suppression of p21 CIP1 and p27KIP1. The CDK2, HAT1 and MYST2 were, however, unaffected in the above study. Using SphK inhibitor and specific siRNA targeting either SphK1 or SphK2, we also unequivocally established that SphK1, but not SphK2, promotes H2691 mesothelioma cell proliferation. Using a multi-walled carbon nanotubes induced peritoneal mesothelioma mouse model, we showed that the SphK1?/? null mice exhibited significantly less inflammation and granulamatous nodules compared to their wild type counterparts. Conclusions/Significance The lipid kinase SphK1 plays a positive and essential role in the growth and development of malignant mesothelioma and is therefore a likely therapeutic target.
Evolution of -Cell Replacement Therapy in Diabetes Mellitus: Islet Cell Transplantation  [PDF]
Cyrus Jahansouz,Cameron Jahansouz,Sean C. Kumer,Kenneth L. Brayman
Journal of Transplantation , 2011, DOI: 10.1155/2011/247959
Abstract: Diabetes mellitus remains one of the leading causes of morbidity and mortality worldwide. According to the Centers for Disease Control and Prevention, approximately 23.6 million people in the United States are affected. Of these individuals, 5 to 10% have been diagnosed with Type 1 diabetes mellitus (T1DM), an autoimmune disease. Although it often appears in childhood, T1DM may manifest at any age, leading to significant morbidity and decreased quality of life. Since the 1960s, the surgical treatment for diabetes mellitus has evolved to become a viable alternative to insulin administration, beginning with pancreatic transplantation. While islet cell transplantation has emerged as another potential alternative, its role in the treatment of T1DM remains to be solidified as research continues to establish it as a truly viable alternative for achieving insulin independence. In this paper, the historical evolution, procurement, current status, benefits, risks, and ongoing research of islet cell transplantation are explored.
Evolution of -Cell Replacement Therapy in Diabetes Mellitus: Islet Cell Transplantation  [PDF]
Cyrus Jahansouz,Cameron Jahansouz,Sean C. Kumer,Kenneth L. Brayman
Journal of Transplantation , 2011, DOI: 10.1155/2011/247959
Abstract: Diabetes mellitus remains one of the leading causes of morbidity and mortality worldwide. According to the Centers for Disease Control and Prevention, approximately 23.6 million people in the United States are affected. Of these individuals, 5 to 10% have been diagnosed with Type 1 diabetes mellitus (T1DM), an autoimmune disease. Although it often appears in childhood, T1DM may manifest at any age, leading to significant morbidity and decreased quality of life. Since the 1960s, the surgical treatment for diabetes mellitus has evolved to become a viable alternative to insulin administration, beginning with pancreatic transplantation. While islet cell transplantation has emerged as another potential alternative, its role in the treatment of T1DM remains to be solidified as research continues to establish it as a truly viable alternative for achieving insulin independence. In this paper, the historical evolution, procurement, current status, benefits, risks, and ongoing research of islet cell transplantation are explored. 1. Introduction In part one of this two-part paper, pancreas transplantation was explored as the definitive treatment for patients with Type 1 diabetes mellitus (T1DM) [1]. It is estimated that of the 23.6 million people diagnosed with diabetes mellitus, 5–10% consist of patients with T1DM [2]. Moreover, recent reports indicate that the incidence of T1DM is increasing, with one study predicting an increase of 70% in those under the age of 15 by 2020 [3–6]. Accordingly, the significant population already afflicted with this disease compounded by the increasing incidence worldwide will have a tremendous impact on future healthcare both domestically and globally [7]. Estimates show that patients with T1DM treated with intensive medical management have six- to sevenfold higher direct cost than age-matched nondiabetics [8]. Although cost is a concern, it is the long-term complications of T1DM that result in the extensive morbidity in this population which fuel the desire for viable alternative treatments from the standard of care, intensive insulin therapy [9]. Even with the mainstay treatment, patients are still at significant risk for complications including retinopathy, neuropathy, nephropathy, coronary artery disease, peripheral vascular disease, and cerebral vascular disease. While the etiology of this disease remains elusive, it is believed that a relationship exists between genetic susceptibility and environmental factors, including infections and toxins, which results in its fulminant presentation [10, 11]. The quest for a surgical
Synergistic Effect of Hyperglycemia and Suppression on Adult Mouse Islet Beta Cell Replication
Szu-Tah Chen,Shin-Huei Fu,Samuel Hsu,Yu-Yao Huang,Brend Ray-Sea Hsu
International Journal of Endocrinology , 2012, DOI: 10.1155/2012/417390
Abstract: The complementary role of hyperglycemia and p27kip1 suppression on islet beta cell regeneration was investigated in a syngeneic mouse model. p27kip1 gene silencing was performed by infecting islets of C57BL/6 with shRNA lentiviral particles. At 54 hours after viral infection, p27kip1 protein content in cultured targeting islets was 22% of that in freshly isolated islets. Six days after transplantation to diabetic mice, targeting islet graft had considerably more cells with Ki67-staining nuclei than nontargeting islets. The mice in the targeting-islet group had a significantly shorter duration of temporary hyperglycaemia than mice in the non-targeting-islet group. The long-term ex vivo beneficial effect of p27kip1 silencing on graft function was also indicated by the significantly higher cumulative cure rate for diabetes in mice receiving 200 targeting islets than that in mice receiving 200 non-targeting islets. Our data suggest that hyperglycemia and persistent p27kip1 suppression have a synergistic effect on islet beta cell replication in adult mice.
Two-layer cold storage method for pancreas and islet cell transplantation  [cached]
Yasuhiro Fujino
World Journal of Gastroenterology , 2010,
Abstract: The two-layer cold storage method (TLM) was first reported in 1988, consisting of a perfluorochemical (PFC) and initially Euro-Collins’ solution, which was later replaced by University of Wisconsin solution (UW). PFC is a biologically inert liquid and acts as an oxygen-supplying agent. A pancreas preserved using the TLM is oxygenated through the PFC and substrates are supplied by the UW solution. This allows the pancreas preserved using the TLM to generate adenosine triphosphate during storage, prolonging the preservation time. In a canine model, the TLM was shown to repair and resuscitate warm ischemically damaged pancreata during preservation, improve pancreas graft survival after transplantation, and also improve the islet yield after isolation. Clinical trials using the TLM in pancreas preservation before whole-pancreas transplantation and islet isolation have shown promising outcomes. We describe the role of the TLM in pancreas and islet transplantation.
ISL1 Promotes Pancreatic Islet Cell Proliferation  [PDF]
Ting Guo, Weiping Wang, Hui Zhang, Yinan Liu, Ping Chen, Kangtao Ma, Chunyan Zhou
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022387
Abstract: Background Islet 1 (ISL1), a LIM-homeodomain transcription factor is essential for promoting pancreatic islets proliferation and maintaining endocrine cells survival in embryonic and postnatal pancreatic islets. However, how ISL1 exerts the role in adult islets is, to date, not clear. Methodology/Principal Findings Our results show that ISL1 expression was up-regulated at the mRNA level both in cultured pancreatic cells undergoing glucose oxidase stimulation as well in type 1 and type 2 diabetes mouse models. The knockdown of ISL1 expression increased the apoptosis level of HIT-T15 pancreatic islet cells. Using HIT-T15 and primary adult islet cells as cell models, we show that ISL1 promoted adult pancreatic islet cell proliferation with increased c-Myc and CyclinD1 transcription, while knockdown of ISL1 increased the proportion of cells in G1 phase and decreased the proportion of cells in G2/M and S phases. Further investigation shows that ISL1 activated both c-Myc and CyclinD1 transcription through direct binding on their promoters. Conclusions/Significance ISL1 promoted adult pancreatic islet cell proliferation and probably by activating c-Myc and CyclinD1 transcription through direct binding on their promoters. Our findings extend the knowledge about the crucial role of ISL1 in maintaining mature islet cells homeostasis. Our results also provide insights into the new regulation relationships between ISL1 and other growth factors.
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