Cancer Cells
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Monday May 9th
Room 520B-F |
11:00 - 13:00 |
Moderators: |
E. Jim Delikatny and Kristine Glunde |
11:00 |
54. |
Both the Glutaminolytic
and Reverse Isocitrate Dehyrdogenase Pathways are Important
for De Novo Lipogenesis from Glutamine in Immortilized
Hematapoietic Cells
Anthony Mancuso1,2, Kathryn E Wellen1,
Chao Lu1, Weixia Liu3, Stephen
Pickup3, and Craig B Thompson1,4
1Cancer Biology, University of Pennsylvania,
Philadelphia, PA, United States, 2Radiology,
University of Pennsylvania, Philadelphia, PA, United
States Minor Outlying Islands,3Radiology,
University of Pennsylvania, Philadelphia, PA, United
States, 4Memorial
Sloan Kettering Cancer Center, New York, NY, United
States
We have been studying lipogenesis because of its
importance in mammalian cell growth and proliferation.
Glucose is normally the primary precursor for this
process; however, we have observed that human
glioblastoma cells derive much lipogenic carbon from
glutamine. In this work, we report that immortalized
hematopoietic cells produce lipid from glutamine via
both the glutaminolytic and reverse isocitrate
dehydrogenase (IDH) pathways in the presence of glucose.
In the absence of glucose, the more energy efficient
glutaminolytic pathway was predominant. These results
are fundamentally different from those observed for
glioblastoma cells, which predominantly use the more
energy inefficient reverse IDH pathway, perhaps
compromising efficiency for the sake of rapid
biosynthesis.
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11:12 |
55. |
Lactate-mediated Metabolic
Cooperation between Human Stromal and Breast Cancer Cells
Ellen Ackerstaff1, Brijesh B. Patel2,
Yanique I. Rattigan2, George Sukenick3,
Natalia Kruchevsky1, John W. Glod2,
Jason A. Koutcher1, and Debabrata Banerjee2
1Memorial Sloan-Kettering Cancer Center, New
York, NY, United States, 2The
Cancer Institute of New Jersey, RWJMS, UMDNJ, New
Brunswick, NJ, United States, 3Sloan-Kettering
Institute, New York, NY, United States
We hypothesize that tumor cells recruit stromal cells
and that stromal cells metabolize lactate expelled by
tumor cells into the microenvironment. Human mesenchymal
stem cells (hMSCs) are bone marrow-derived stromal cells
which migrate toward hypoxic tumor cells and overexpress
functional monocarboxylate transporter 1 in response to
lactate exposure. Naive hMSCs and carcinoma-associated
fibroblasts (CAFs) exposed to 13C-3-lactate,
produced detectable levels of 13C-α-ketoglutarate.
Additional 14C-lactate
studies showed that lactate uptake in CAFs was higher
than in hMSCs. Also, lactate stimulated hMSC migration.
Our results suggests the metabolic cooperation between
stromal and tumor cells.
|
11:24 |
56. |
Free Choline Influences
Adaptation Mechanisms in Choline Phospholipid Metabolism of
Human Breast Cancer Cells
Balaji Krishnamachary1, Noriko Mori1,
Mayur Gadiya1, Yelena Mironchik1,
Flonne Wildes1, Kristine Glunde1,
and Zaver M Bhujwalla1
1Radiology, Johns Hopkins University,
Baltimore, Maryland, United States
Synopsis: Increased phosphocholine (PC) and total
choline are consistently observed in cancers, especially
breast cancer. Only now are we beginning to uncover the
complexity of factors that regulate choline metabolism
in cancer, and the compensatory mechanisms that exist in
this pathway. Here we have shown the interdependence
between two enzymes in choline metabolism, choline
kinase (Chk) the enzyme that forms phosphocholine from
free choline, and phosphatidylcholine-specific
phospholipase D1 (PLD1), the enzyme that forms choline
from phosphatidylcholine. We have also identified
increased free choline as an inhibitor of the increase
of PLD1 observed following Chk downregulation.
|
11:36 |
57. |
Effects of targeting the
glycerophosphocholine phosphodiesterase GDPD5 in breast
cancer models
Maria Dung Cao1,2, Lu Jiang1,
Balaji Krishnamachary1, Mailin Doepkens1,3,
Zaver M Bhjuwalla1, Ingrid Gribbestad2,
and Kristine Glunde1
1Russell H. Morgan Department of Radiology
and Radiological Science, Johns Hopkins University
School of Medicine, Baltimore, Maryland, United States, 2Department
of Circulation and Medical Imaging, Norwegian University
of Science and Technology (NTNU), Trondheim, Norway, 3Department
of Chemistry and Biology, University of Bremen, Bremen,
Germany
In our study we investigated the effects of silencing
the glycerophosphocholine phosphodiesterase GDPD5 in
MCF7 breast cancer cells and tumor xenograft models
using both ex vivo high-resolution MRS and in vivo MRSI.
Here we demonstrated for the first time that silencing
the specific GPC-PDE enzyme GDPD5 increased the tCho
levels in breast cancer cells and tumor models.
Interestingly, the tumor growth rate of the
GDPD5-silenced breast tumor xenografts was significantly
reduced. These findings emphasize that GDPD5 may have a
potential role as an anticancer target in regulating
choline phospholipid metabolism in breast cancer.
|
11:48 |
58. |
Effect of the HIF Pathway
Inhibitor NSC-134754 on Glucose Metabolism
Lauren C.J Baker1, Yuen-Li Chung1,
Jessica K Boult1, Margaret A Ashcroft2,
and Simon P Robinson1
1CRUK and EPSRC Cancer Imaging Centre, The
Institute of Cancer Research and Royal Marsden NHS
Trust, Sutton, Surrey, United Kingdom, 2University
College London, United Kingdom
Hypoxia-inducible factor (HIF) pathway inhibitors are an
emerging class of therapeutics, whose precise mechanism
of action is unclear. In this study, we examined the
metabolic effects of NSC-134754, a small molecule
inhibitor of the HIF pathway. Firstly, we show that
NSC-134754 downregulates both the expression and
distribution of glucose transporter 1, a downstream
target of HIF-1. Secondly, magnetic resonance
spectroscopy reveals a unique metabolic profile of the
actions of NSC-134754 on cellular metabolism. Finally,
we demonstrate that effects on glucose transport in
vitro with
NSC-134754 are reproduced in
vivo in
an orthotopic model of prostate cancer.
|
12:00 |
59. |
Magnetic resonance
spectroscopy metabolic profiling reveals different
mechanisms of action in response to signaling inhibitors in
prostate cancer
Alessia Lodi1, and Sabrina M Ronen1
1University of California San Francisco, San
Francisco, California, United States
Carcinogenesis often involves signaling pathway
deregulation and targeted inhibitors are under
investigation as anticancer therapeutics. Here we used a
completely untargeted, MRS-based metabolomics approach
to investigate the metabolic consequences of treatment
with PI3K or combined PI3K/MAPK inhibitors in human
prostate cancer cells. The modulation of phosphocholine
and lactate concentrations following treatment with
either PI3K or combined PI3K/MAPK inhibitors was similar
in different prostate cell lines and recapitulated
similar findings in breast cancer cells. Interestingly
treatment of prostate cells with 17AAG increased the
accumulation of citrate, a key metabolite dramatically
decreased upon prostate malignant transformation.
|
12:12 |
60. |
Comparing the
Chemotherapeutic Response of Prostate Cancer Cells using
MR-visible Lipids and Fluorescent Fatty Acid Incorporation -permission
withheld
Daniel-Joseph Leung1,2, and E. James
Delikatny2
1Department of Pharmacology, University of
Pennsylvania, Philadelphia, PA, United States, 2Department
of Radiology, University of Pennsylvania, Philadelphia,
PA, United States
Observations of intracellular lipid (particularly
triglyceride) accumulation in the form of MR-visible
mobile lipids and lipid droplets have been associated
with apoptosis and necrosis in a variety of cancer
models. Here we use MRS in combination with fluorescent
fatty acids to assess the process of mobile lipid
formation in DU145 prostate cancer cells. This assay is
then used to screen DU145 cells against a range of
anticancer drugs, resulting in measured fluorescence
indicative of a range of lipid response. This approach,
used as a screening tool in conjunction with MRS, will
aid in the functional dissection of the contributing
pathways involved in lipid formation in cancer cells
undergoing chemotherapy.
|
12:24 |
61. |
Noninvasive Assessment of
Renal Tumor Aggressiveness using Hyperpolarized
13C MR -permission
withheld
Kayvan R. Keshari1, Bertram Koelsch2,
Rahwa Iman2, Mark Van Criekinge2,
Daniel B. Vigneron2, John Kurhanewicz2,
and Zhen J Wang2
1UCSF, San Francisco, CA, United States, 2UCSF
The widespread use of cross-sectional imaging has led to
the incidental discovery of many renal tumors. However,
triage of therapies is currently difficult due to our
inability to reliably differentiate benign from
malignant, or indolent from aggressive renal tumors
noninvasively by conventional imaging techniques. In
this study we use a combination steady-state
[3-13C]pyruvate cell labeling and HP [1-13C]pyruvate
cell culture bioreactor studies to show that HP13C MR
has the potential to noninvasively characterize renal
tumor aggressiveness. Specifically, increasing HP
[1-13C]lactate may be a useful biomarker for
discriminating benign from malignant, and indolent from
aggressive renal tumors.
|
12:36 |
62. |
1H MRS and
Hyperpolarised 13C
MRS Assays of Pyruvate-Lactate Exchange in SW1222 Cancer
Cells In Vitro
Deborah Katherine Hill1, Yann Jamin1,
Nicolas Tardif1, Anne-Christine Wong Te Fong1,
Simon P Robinson1, Harold G Parkes1,
Matthew R Orton1, Martin O Leach1,
Yuen-Li Chung1, and Thomas R Eykyn1,2
1Clinical Magnetic Resonance, CRUK and EPSRC
Cancer Imaging Centre, Royal Marsden NHS Trust and The
Institute of Cancer Research, Sutton, Surrey, United
Kingdom,2Division of Imaging Sciences, The
Rayne Institute, Lambeth Wing, St Thomas Hospital,
London, United Kingdom
Signal enhancements by DNP have facilitated the
interrogation of metabolic processes using 13C
MRS in real-time. We demonstrate that it is possible to
measure in
vitropyruvate-lactate exchange kinetics by utilising
scalar couplings of methyl 1H
resonances to adjacent [3-13C] labelled
nuclei, without the need of hyperpolarisation. The 1H
MRS-based assay measured the forward reaction rate with
comparable reproducibility to the hyperpolarised 13C
assay. The 1H
assay has the advantage of also reliably probing the
backward reaction, which has large errors in the 13C
assay. Both assays detected a comparable response to
treatment with Paclitaxel, a widely used chemotherapy
drug.
|
12:48 |
63. |
Metabolism of
Hyperpolarized U-13C-d7-D-Glucose in
Living Breast Cancer Cell Cultures
Talia Harris1, Lucio Frydman1, and
Hadassa Degani2
1Chemical Physics, Weizmann Institute of
Science, Rehovot, Israel, 2Biological
Regulation, Weizmann Institute of Science, Rehovot,
Israel
Elevated glycolytic rates are a known feature of many
cancers. The recent development of a method to
hyperpolarize nuclear spins more than 10,000x in the
liquid states opens up new opportunities to follow
metabolic processes non-invasively with high temporal
resolution using 13C NMR. In this study we utilize a
perfusion-injection system to study the metabolism of
hyperpolarized U-13C-d7-D-Glucose in living T47D breast
cancer cells. The conversion of Glucose Lactate as well
as labeling of other metabolites is seen. Further, the
conversion of GlucoseLactate by T47D cells is shown to
have the same concentration dependence as the uptake of
radioactively labeled 2-deoxy-D-Glucose.
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