CBIO-06. CELL INTRINSIC HFE DRIVES SEX-SPECIFIC GLIOBLASTOMA GROWTH

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi28-vi28
Author(s):  
Katie M Troike ◽  
Erin E Mulkearns-Hubert ◽  
Daniel J Silver ◽  
James Connor ◽  
Justin Lathia
Keyword(s):  
Tumor Growth ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Status ◽  
Essential Element ◽  
Cell Number ◽  
Hfe Gene ◽  
Dependent Manner

Abstract Iron is an essential element required for a number of cellular processes and can contribute to malignant transformation and tumor expansion. In glioblastoma (GBM), tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The homeostatic iron regulatory (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by modulating iron uptake and release. HFE is upregulated in GBM tumors compared to non-tumor brain and expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. However, it is unclear how HFE impacts sex-specific GBM growth. To interrogate the underlying mechanism of HFE-mediated sex differences, we employed genetic loss and gain of function approaches using syngeneic mouse glioma models. We observed significant alterations in the expression of several iron-associated genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. We found that knockdown of Hfe decreased cell number and increased apoptosis in vitro and led to a significant impairment of tumor growth in vivo, with a more pronounced effect seen in female mice. Conversely, overexpression of Hfe increased cell number and significantly decreased survival only in female animals. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression in a sex-dependent manner. These data also suggest an unexplored link between cell intrinsic iron signaling and sex-specific microenvironmental and immune responses, which is the focus of ongoing studies.

scholarly journals CBIO-10. REDUCED IRON EXPORT FUNCTIONS IN A CELL INTRINSIC MANNER TO DRIVE GLIOBLASTOMA GROWTH

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
Katie Troike ◽  
Erin Mulkearns-Hubert ◽  
Daniel Silver ◽  
James Connor ◽  
Justin Lathia
Keyword(s):  
Tumor Cells ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Status ◽  
Tumor Grade ◽  
Hfe Gene ◽  
Iron Release ◽  
Female Patients ◽  
Cellular Iron

Abstract Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is characterized by invasive growth and poor prognosis. Iron is a critical regulator of many cellular processes, and GBM tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving tumor initiation and growth. While iron uptake has been the central focus of previous investigations, additional mechanisms of iron regulation, such as compensatory iron efflux, have not been explored in the context of GBM. The hemochromatosis (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by limiting cellular iron release, resulting in a sequestration phenotype. We find that HFE is upregulated in GBM tumors compared to non-tumor brain and that expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. Based on these findings, we hypothesize that GBM tumor cells upregulate HFE expression to augment cellular iron loading and drive proliferation, ultimately leading to reduced survival of female patients. To test this hypothesis, we generated Hfe knockdown and overexpressing mouse glioma cell lines. We observed significant alterations in the expression of several iron handling genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. Additionally, we show that knockdown of Hfe in these cells increases apoptosis and leads to a significant impairment of tumor growth in vivo. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression. Future work will include further exploration of the mechanisms that contribute to these phenotypes as well as interactions with the tumor microenvironment. Elucidating the mechanisms by which iron effulx contributes to GBM may inform the development of next-generation targeted therapies.

scholarly journals Dopamine Is a Siderophore-Like Iron Chelator That PromotesSalmonella entericaSerovar Typhimurium Virulence in Mice

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Stefanie Dichtl ◽  
Egon Demetz ◽  
David Haschka ◽  
Piotr Tymoszuk ◽  
Verena Petzer ◽  
...  
Keyword(s):  
Bacterial Growth ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Lipocalin 2 ◽  
Intracellular Iron ◽  
Content Type ◽  
Hepcidin Expression

ABSTRACTWe have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course ofSalmonellainfections. Dopamine was found to promote the growth ofSalmonellaboth in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected withSalmonella entericaserovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth.Salmonellalacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria.IMPORTANCEHere we show that dopamine increases bacterial iron incorporation and promotesSalmonellaTyphimurium growth bothin vitroandin vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13093-13093 ◽  
Author(s):  
S. L. Smiley ◽  
D. O. Henry ◽  
M. K. Wong
Keyword(s):  
Endothelial Cells ◽  
Tumor Growth ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Receptor System ◽  
Fgf Receptor ◽  
Tumor Inhibition ◽  
Inhibition Of Tumor Growth

13093 Background: Clinical studies show that LMWHs improve survival in cancer patients. There is compelling and mounting evidence that non-anticoagulation factors are at play, and that these may be contributing in a major way to improved patient outcome. Methods and Results: Dalteparin, enoxaparin, and tinzaparin were tested for their in vivo ability to inhibit tumor lines engineered for aggressive angiogenesis-driven growth. Therapeutic daily doses of drug administered the day following tumor inoculation resulted in significant angiogenesis and tumor inhibition. We previously showed that LMWHs inhibit fibroblast growth factor (FGF) -induced mitogenesis of Tumor Derived Endothelial Cells (TDECs) in a time and concentration dependent manner in vitro. We now show that this endothelial inhibition occurs through LMWHs-mediated reduction of phosphorylation and down stream signaling through ERK. The potency of LMWH was significantly reduced when TDECs were pretreated with heparinase- suggesting that the molecular target for LMWH may be the cell surface, low affinity FGF receptor system. Both our in vivo and in vitro studies demonstrate that angiogenesis and tumor inhibition are greatest for dalteparin > tinzaparin > enoxaparin. Clues to the heparin-TDECs interaction comes from tracking the real-time movement of FGF using a highly fluorescent nanocrystal bead decorated on its surface with FGF. High resolution video-microscopy shows FGF binding onto TDEC surfaces, but once heparin enters the environment, FGF detaches from the TDECs and migrates to the heparin. This ultimately results in significant TDEC growth inhibition as compared to controls. Conclusion: LMWH treatment at pharmacologic doses significantly blunts tumor growth and angiogenesis. This inhibition resides in part via heparin’s ability to sequester FGF from the low affinity receptor system on tumor endothelial cells. No significant financial relationships to disclose.

scholarly journals Cytotoxic effect of Montivipera bornmuelleri’s venom on cancer cell lines: in vitro and in vivo studies

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9909
Author(s):  
Carol Haddoub ◽  
Mohamad Rima ◽  
Sandrine Heurtebise ◽  
Myriam Lawand ◽  
Dania Jundi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
In Vivo Testing ◽  
Murine Fibrosarcoma ◽  
Dose Dependent

Background Montivipera bornmuelleri’s venom has shown immunomodulation of cytokines release in mice and selective cytotoxicity on cancer cells in a dose-dependent manner, highlighting an anticancer potential. Here, we extend these findings by elucidating the sensitivity of murine B16 skin melanoma and 3-MCA-induced murine fibrosarcoma cell lines to M. bornmuelleri’s venom and its effect on tumor growth in vivo. Methods The toxicity of the venom on B16 and MCA cells was assessed using flow cytometry and xCELLigence assays. For in vivo testing, tumor growth was followed in mice after intratumoral venom injection. Results The venom toxicity showed a dose-dependent cell death on both B16 and MCA cells. Interestingly, overexpression of ovalbumin increased the sensitivity of the cells to the venom. However, the venom was not able to eradicate induced-tumor growth when injected at 100 µg/kg. Our study demonstrates a cytotoxic effect of M. bornmuelleri’s venom in vitro which, however, does not translate to an anticancer action in vivo.

scholarly journals 4SC-202 Exerts An Anti-tumor Effect in Cervical Cancer By Targeting PRLR Signaling Pathway

2021 ◽  
Author(s):  
Huijuan Zhang ◽  
Mingxia Li ◽  
Wen Yang ◽  
Mingxia Ye ◽  
Hua Li ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Tumor Growth ◽  
Western Blotting ◽  
Prolactin Receptor ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Siha Cells ◽  
Serum Biochemical

Abstract The aim of the present study is to investigate whether 4SC-202, a selective class I histone deacetylase inhibitor (HDACi), plays an anti-tumor role in cervical cancer (CC) by targeting prolactin receptor (PRLR). CCK-8 and colony formation assays were used to evaluate the effects of 4SC-202 on the proliferation of CC cells in vitro. Effects of 4SC-202 on the cell cycle distribution and apoptosis in SiHa cells were determined by flow cytometry and western blotting, respectively. Immunofluorescence and western blotting were performed to detect the activities of PRLR-related pathways and PRLR expression in CC cells. A xenograft tumor model in nude mice was established to examine effects of 4SC-202 on the tumor growth, apoptosis and PRLR-related pathways in vivo. The biochemical analyzer and H&E staining were used to detect the serum biochemical indexes and organ toxicity. 4SC-202 inhibited the proliferation of CC cells (SiHa, HeLa, and CaSki) in vitro in a time- and dose-dependent manner. SiHa cells were treated with 1 or 5 μM 4SC-202 for 72 h and then subjected to various functional assays. The assays showed that 4SC-202 significantly induced G2/M phase arrest and apoptosis, while inhibiting the activities of PRLR-related pathways and PRLR expression. In addition, 4SC-202 reduced tumor growth and induced apoptosis in vivo. 4SC-202 down-regulated the expression of PRLR and activities of PRLR-related pathways in the mouse model, displayed no effects on serum biochemical indicators and caused no toxicity to mouse organs. This finding suggests that 4SC-202 may serve as a novel therapeutic agent for CC.

Regulation of mouse placental lactogen secretion by factors secreted from the pituitary in vitro

1996 ◽  
Vol 134 (1) ◽  
pp. 123-127 ◽  
Author(s):  
Masaaki Yamaguchi ◽  
Akira Miyake
Keyword(s):  
Conditioned Medium ◽  
Northern Blot Analysis ◽  
Cell Number ◽  
Placental Lactogen ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Placental Cells ◽  
A Cell

Yamaguchi M. Miyake A. Regulation of mouse placental lactogen secretion by factors secreted from the pituitary in vitro. Eur J Endocrinol 1996;134:123–7. ISSN 0804–4643 The effect of factors secreted from the pituitary on mouse placental lactogen I (mPL-I) and mPL-II secretion in vitro was examined. Co-culture of mouse placental cells from day 7 of pregnancy with the pituitary cells of the mother significantly stimulated mPL-I secretion but did not regulate mPL-II secretion. The effect on mPL-I secretion was dependent on the number of pituitary cells. The conditioned medium of pituitary cells also significantly stimulated mPL-I secretion but did not regulate mPL-II secretion. The stimulatory effect of mPL-I secretion was dependent on the volume of the conditioned medium. The number of cells containing mPL-I assessed by immunocytochemistry was increased by the co-culture in a cell number-dependent manner. Northern blot analysis for mPL-I indicated that treatment of placental cells with the pituitary-conditioned medium results in an increase of mPL-I gene expression. These findings suggest that factors secreted from the pituitary directly regulate mPL-I secretion, but not mPL-II secretion, before midpregnancy in vivo. Masaaki Yamaguchi, Department of Obstetrics and Gynecology. Osaka University Medical School, 2-2 Yamadaoka, Suita. Osaka 565, Japan

Studies of pemetrexed and gemcitabine, alone and in combinations, in human lung cancer models

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17114-17114 ◽  
Author(s):  
D. C. Chan ◽  
V. J. Chen ◽  
Z. Zhang ◽  
B. Helfrich ◽  
F. R. Hirsch ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
In Vivo Studies ◽  
Human Lung Cancer ◽  
Dependent Manner ◽  
Antitumor Effects ◽  
Nude Rats ◽  
Combination Regimens

17114 Background: Gemcitabine (GEM) is a deoxycytidine analog that inhibits DNA synthesis. Pemetrexed (ALIMTA, PEM) is a novel antifolate inhibiting multiple enzymes targets, including thymidylate synthase (TS). This study aimed at evaluating the antitumor effects of these antimetabolites against NSCLC and SCLC tumor models. Methods: In vitro growth inhibition (IC50) studies were done by 6-days MTT assays against a panel of 20 NSCLC and 17 SCLC cell lines. In vivo studies used only NSCLC H2122 tumor line, implanted either subcutaneously in athymic nude mice or orthotopically in athymic nude rats. Drugs were given via the ip route at the designated schedules. Results: Against NSCLC and SCLC cell lines, the averaged IC50s of GEM were 0.015 ± 0.008 μM and 0.055 ± 0.04 μM respectively. The corresponding averaged IC50s for PEM were 0.65 ± 0.2 μM and 0.091±0.018 μM respectively. When H2122 tumors reached 50–100mg, mice were treated with 10 daily doses of PEM at 100, 200 and 300 mg/kg, or three doses of GEM every 4 days at 30, 60 and 120 mg/kg. PEM delayed tumor growth by 12 to 18 days, and GEM delayed by 10 to 14 days, relative to vehicle control. Results of three combination regimens with GEM (30 mg/kg) and PEM (100 mg/kg) were: (1) GEM → PEM gave intermediate activities between the two single agents, but was toxic to animals; (2) PEM and GEM given concurrently were more active than single agents alone and delayed tumor growth by 12 days with some toxic side effects; (3) PEM → GEM was better than the single agents alone, and delayed tumor growth by ∼14 days without toxicity. Athymic nude rats bearing orthotopic H2122 tumors given PEM daily at 50, 100 and 200 mg/kg for 21 days had significantly prolonged survival, but not in a dose-dependent manner. PEM at 50 mg/kg was more effective than doses at 100 or 200 mg/kg. GEM was toxic to nude rats due to poor plasma deamination of GEM. Conclusions: In vitro, PEM was more potent against SCLC than NSCLC cell lines, but GEM had similar activities against all lung lines tested. Studies of H2122 xenografts in rodent supported PEM → GEM as the preferred sequence for the combined administration of these two drugs. [Table: see text]

Efficacy of adavosertib therapy against anaplastic thyroid cancer

2021 ◽  
Author(s):  
Yu-Ling Lu ◽  
Yu-Tung Huang ◽  
Ming-Hsien Wu ◽  
Ting-Chao Chou ◽  
Richard J Wong ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Tumor Growth ◽  
Single Agent ◽  
Xenograft Model ◽  
Anaplastic Thyroid Cancer ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Cancer Tumor

Wee1 is a kinase that regulates the G2/M progression by inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.

Synergic Effects of Proteasome Inhibitor PS-341 and Tyrosine Kinase Inhibitor STI571 on Chronic Myeloid Leukemia Cells and BCR-ABL Oncoprotein In Vitro and In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4771-4771
Author(s):  
Guangbiao Zhou ◽  
Zheng Hu ◽  
Dapeng Liu ◽  
Fuqun Wu ◽  
Jiang Zhu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tumor Growth ◽  
Proteasome Inhibitor ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Great Promise ◽  
Dependent Manner

Abstract STI571/Gleevec/imatinib, a rationally-designed agent that occupies the ATP-binding site of BCR-ABL and stabilizes the protein in its closed, inactive conformation, has been a remarkable success for the treatment of chronic myeloid leukemia (CML). However, a significant proportion of patients chronically treated with STI571 develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Furthermore, the effects of STI571 on CML patients in accelerated phase or blastic crisis are unsatisfactory since many patients relapse after transient remission. Hence, additional drugs or STI571-based combination regimens are desired to circumvent resistance and to improve response rates. Here we reported that PS-341, a proteasome inhibitor which offers great promise to patients with multiple myeloma (MM), significantly enhanced the antileukemia activity of STI571 in vitro and in vivo. We found a synergy exists between low concentrations of PS-341 (5–10 nM) and STI571 (0.1–0.2 μM) in inhibition of cell growth and induction of apoptosis in K562 cell line and CD34+ leukemic cells isolated from CML patients. In K562 cells, combined use of PS-341 and STI571 accelerated activation of caspase-3, 9, and facilitated cleavage of poly-(ADP-ribose) polymerase (PARP) as compared to those in cells treated with PS-341 or STI571 alone. Moreover, PS-341/STI571 combination resulted in potentiated degradation of BCR-ABL and downregulation of phosphorylated BCR-ABL as compared to those in mono treatment. In nude mice inoculated subcutaneously with K562 cells, treatment with PS-341 (injected intraperitoneally, ip) alone (at doses of 0.05, 0.5, 1 mg/kg/d, twice a week for 4 weeks, respectively) decreased tumor growth in a dose-dependent manner. STI571 (ip) at 10 mg/kg/d also inhibited tumor growth. Intriguingly, combinatory administration of low dose PS-341 (0.05 mg/kg/d, twice a week for 4 weeks) and STI571 (10 mg/kg/d) yielded a much more profound inhibition of tumor growth and even clearance of leukemic cells in mice compared to either monotherapy. Taken together, these results demonstrate synergic effects of PS-341 and STI571, and provide the rationale to evaluate PS-341/STI571 combination in treating CML aiming to further improve clinical outcome of patients.

scholarly journals Preptin, another peptide product of the pancreatic β-cell, is osteogenic in vitro and in vivo

2007 ◽  
Vol 292 (1) ◽  
pp. E117-E122 ◽  
Author(s):  
J. Cornish ◽  
K. E. Callon ◽  
U. Bava ◽  
M. Watson ◽  
X. Xu ◽  
...  
Keyword(s):  
Bone Mass ◽  
Map Kinases ◽  
Cell Number ◽  
Dependent Manner ◽  
Pancreatic Β Cell ◽  
Hepatitis C Infection ◽  
Β Cell ◽  
High Bone Mass

Several hormones that regulate nutritional status also impact on bone metabolism. Preptin is a recently isolated 34-amino acid peptide hormone that is cosecreted with insulin and amylin from the pancreatic β-cells. Preptin corresponds to Asp69-Leu102 of pro-IGF-II. Increased circulating levels of a pro-IGF-II peptide complexed with IGF-binding protein-2 have been implicated in the high bone mass phenotype observed in patients with chronic hepatitis C infection. We have assessed preptin's activities on bone. Preptin dose-dependently stimulated the proliferation (cell number and DNA synthesis) of primary fetal rat osteoblasts and osteoblast-like cell lines at periphysiological concentrations (>10−11 M). In addition, thymidine incorporation was stimulated in murine neonatal calvarial organ culture, likely reflecting the proliferation of cells from the osteoblast lineage. Preptin did not affect bone resorption in this model. Preptin induced phosphorylation of p42/p44 MAP kinases in osteoblastic cells in a dose-dependent manner (10−8-10−10 M), and its proliferative effects on primary osteoblasts were blocked by MAP kinase kinase inhibitors. Preptin also reduced osteoblast apoptosis induced by serum deprivation, reducing the number of apoptotic cells by >20%. In vivo administration of preptin increased bone area and mineralizing surface in adult mice. These data demonstrate that preptin, which is cosecreted from the pancreatic β-cell with amylin and insulin, is anabolic to bone and may contribute to the preservation of bone mass observed in hyperinsulinemic states such as obesity.

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