EDITOR'S PICK: How to overcome resistance to one group of breast
cancer drugs
A team of researchers, led by Carlos Arteaga, at Vanderbilt
University Medical Center, Nashville, has identified a mechanism by
which human breast cancer cells can develop resistance to one group
of drugs used to treat breast cancer, suggesting new approaches to
treating the disease.
A large proportion of breast cancers express the molecule to
which the sex hormone estrogen binds and show a degree of
dependence on the hormone for growth. Patients with such tumors are
usually treated with drugs known as endocrine therapies that
interfere with estrogen signaling to the tumor cell. However, some
cancers develop resistance to endocrine therapies after initially
responding. To define mechanisms underlying the development of
resistance to endocrine therapies, Arteaga and colleagues analyzed
molecular changes in human breast cancer cell lines subject to
long-term estrogen deprivation (a condition that mimics an
endocrine therapy regimen). They found evidence of PI3K signaling
pathway activation, and cells treated with a PI3K inhibitor died.
As a breast tumor protein signature of PI3K pathway activation was
found to predict poor outcome after endocrine therapy in patients,
the authors suggest that combining an endocrine therapy with a PI3K
pathway inhibitor might help prevent the development of resistance
to endocrine therapies in patients with breast cancer.
TITLE: Hyperactivation of phosphatidylinositol-3 kinase promotes
escape from hormone dependence in estrogen receptor–positive
human breast cancer
AUTHOR CONTACT:
Carlos L. Arteaga
Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt
University, Nashville, Tennessee, USA.
Phone: 615.936.3524; Fax: 615.936.1790; E-mail:
carlos.arteaga@vanderbilt.edu.
View this article at:
http://www.jci.org/articles/view/41680?key=9e3ff18962ef2def510c
EDITOR'S PICK: Reducing the toxicity of lithium
Lithium is the most effective treatment for bipolar disorder.
However, its use is limited because of neurological side effects
and a risk for overdose-induced toxicity. Many of the beneficial
effects of lithium are mediated by its inhibition of GSK-3
proteins, but whether this is the mechanism underlying its negative
effects has not been determined. However, Raquel
Gómez-Sintes and José Lucas, at CSIC/UAM, Spain, have
now delineated a molecular pathway by which chronic administration
of therapeutic doses of lithium has negative effects in mice.
Specifically, they found that gait abnormalities and nerve cell
death in several regions of the brain were a result of GSK-3
protein inhibition, which led to increased nuclear localization of
NFATc3/4 proteins and increased levels of the death-inducing
molecule Fas ligand. The authors hope that these data might provide
new ideas for combination therapies that diminish the toxicities of
lithium, which has been proposed as a treatment for Alzheimer
disease.
TITLE: NFAT/Fas signaling mediates the neuronal apoptosis and
motor side effects of GSK-3 inhibition in a mouse model of lithium
therapy
AUTHOR CONTACT:
José J. Lucas,
Centro de Biología Molecular "Severo Ochoa," CSIC/UAM,
Madrid, Spain.
Phone: 34.91.196.4552, 34.91.196.4582; Fax: 34.91.196.4420; E-mail:
jjlucas@cbm.uam.es.
View this article at:
http://www.jci.org/articles/view/37873?key=6336b61bbbea56ebf13c
METABOLIC DISEASE: Antidiabetic drugs learn their
ABCG(1)s
Cholesterol is often thought of as bad for us, but it is
actually an essential component of cell membranes. Cellular
cholesterol levels and distribution are therefore tightly
regulated, and the protein ABCG1 has an important role in the
regulation process. Now, a team of researchers, led by Catherine
Hedrick, at the La Jolla Institute for Allergy and Immunology, La
Jolla, has generated data indicating that pancreatic beta cell
expression of ABCG1 is reduced in diabetic mice and that its
expression can be restored by treatment with antidiabetic drugs
known as TZDs. These and other data in the study implicate altered
pancreatic beta cell expression of ABCG1 has having a role in
diabetes and suggest that restoration of normal levels of
expression is a component of the therapeutic effect of TZDs.
TITLE: An intracellular role for ABCG1-mediated cholesterol
transport in the regulated secretory pathway of mouse pancreatic
beta cells
AUTHOR CONTACT:
Catherine C. Hedrick
La Jolla Institute for Allergy and Immunology, La Jolla,
California, USA.
Phone: 858.752.6604; Fax: 858.752.6985; E-mail:
hedrick@liai.org.
View this article at:
http://www.jci.org/articles/view/41280?key=8c2f06fe1dfa63c77b94
ONCOLOGY: Putting cancer in a PINCH(1) to overcome resistance
to radiation therapy
One of the main obstacles to complete elimination of a cancer is
tumor cell resistance to ionizing radiation therapy and
chemotherapy. One factor contributing to this is tumor cell
adhesion to the surrounding tissue matrix mediated by large protein
complexes known as focal adhesions. A team of researchers, led by
Nils Cordes, at OncoRay — Center for Radiation Research in
Oncology, Germany, has now identified one signaling pathway that
functions downstream of focal adhesions to promote tumor cell
resistance to ionizing radiation. The pathway is initiated by
elevated levels of the protein PINCH1 and has a prosurvival effect,
enhancing the resistance of tumor cells to ionizing radiation. As
mouse cells lacking PINCH1 showed enhanced sensitivity to ionizing
radiation in vitro and in vivo, the authors suggest that targeting
molecules in this pathway such as PINCH1 might provide new
therapeutic approaches to overcoming tumor cell resistance to
ionizing radiation therapy.
TITLE: PINCH1 regulates Akt1 activation and enhances
radioresistance by inhibiting PP1-alpha
AUTHOR CONTACT:
Nils Cordes
OncoRay — Center for Radiation Research in Oncology, Dresden
University of Technology, Dresden, Germany.
Phone: 351.458.7401; Fax: 351.458.7311; E-mail:
Nils.Cordes@Oncoray.de.
View this article at:
http://www.jci.org/articles/view/41078?key=388cef8b331baca82b20
ONCOLOGY: To promote tumors or to protect from them, that is
the question for NF-kappa-B
The role of the gene regulatory protein NF-kappa-B in tumor
development is controversial — some studies suggest it
promotes tumor development while others indicate it has a
protective effect — and seems to vary depending on the tumor.
A team of researchers, led by Ann Richmond, at Vanderbilt
University School of Medicine, Nashville, now clearly shows that
NF-kappa-B activity is required for tumor formation in a mouse
model of melanoma (the most dangerous form of skin cancer). As
protection against tumor formation was observed in mice lacking the
protein IKK-beta, an inhibitor of the NF-kappa-B inhibitor
I-kappa-B, the authors suggest that IKK-beta might be a good
therapeutic target for melanoma.
TITLE: Conditional ablation of Ikkb inhibits melanoma tumor
development in mice
AUTHOR CONTACT:
Ann Richmond
Vanderbilt University School of Medicine, Nashville, Tennessee,
USA.
Phone: 615.343.7777; Fax: 615.936.2911; E-mail:
ann.richmond@vanderbilt.edu.
View this article at:
http://www.jci.org/articles/view/42358?key=0884ba803e0eba81c952
BONE BIOLOGY: The protein ESL-1 regulates TGF-beta
Skeletal dysplasias, conditions sometimes called dwarfism, are a
group of congenital abnormalities of the bone and cartilage that
are characterized by short stature. Most are caused by
dysregulation at growth plates, areas of developing cartilage near
the ends of long bones that regulate and help determine the length
and shape of the mature bone. In many instances, growth plate
dysregulation is a result of disruption in the TGF-beta signaling
pathway. A team of researchers, led by Brendan Lee, at Baylor
College of Medicine, Houston, has now identified in mice a new
intracellular mechanism for regulating TGF-beta during skeletal
development and maintenance. Specifically, they find that the
protein ESL-1 acts as a negative regulator of TGF-beta production
by binding TGF-beta precursors and inhibiting their maturation. As
TGF-beta signaling pathway dysregulation has a role in medical
conditions such as cancer and immune disorders, the authors suggest
their data have far reaching clinical implications and that
targeting ESL-1 might provide a new therapeutic approach for many
conditions.
TITLE: E-selectin ligand regulates growth plate
homeostasis in mice by inhibiting the intracellular processing and
secretion of mature TGF-beta
AUTHOR CONTACT:
Brendan Lee
Baylor College of Medicine, Houston, Texas, USA.
Phone: 713.798.8835; Fax: 713.798.5168; E-mail:
blee@bcm.edu.
View this article at:
http://www.jci.org/articles/view/42150?key=483adf9524db4d8cba12
INFLAMMATION: New inflammation-modulating function for the
peptide hormone hepcidin
Hepcidin is a peptide hormone with two known functions: it
controls the amount of iron in our bodies and it acts as an
antimicrobal agent. But now, Jerry Kaplan, Ivana De Domenico, and
colleagues, at the University of Utah, Salt Lake City, have
identified a new function for hepcidin in mice. Specifically, they
find that it modulates acute inflammatory responses.
Several lines of evidence support the authors conclusion that
hepcidin can act as an anti-inflammatory agent, including the
observations that hepcidin modulated the expression of genes
induced by inflammatory agents in mice (diminishing expression of
several known pro-inflammatory genes) and that hepcidin
pretreatment protected mice from a lethal dose of the
prinflammatory mediator LPS. Furthermore, the authors suggest that
the persistently high levels of hepcidin that are associated with
chronic inflammatory disorders and known to compromise iron levels
and cause anemia, might also diminish inflammatory responses in
these patients.
TITLE: Hepcidin mediates transcriptional changes that modulate
acute cytokine-induced inflammatory responses in mice
AUTHOR CONTACT:
Jerry Kaplan
University of Utah, Salt Lake City, Utah, USA.
Phone: 801.581.7427; Fax: 801.585.6364; E-mail:
jerry.kaplan@path.utah.edu.
Ivana De Domenico
University of Utah, Salt Lake City, Utah, USA.
Phone: 801.581.7427; Fax: 801.585.6364; E-mail:
ivana.dedomenico@path.utah.edu.
View this article at:
http://www.jci.org/articles/view/42011?key=87e5a94639a84dcc1d19
HEMATOLOGY: Separating the good from the bad in bone marrow
transplantation
Treatment for several forms of leukemia involves a bone marrow
transplant from a genetically nonidentical individual. Immune cells
develop in the patient from the transplanted bone marrow and
destroy the leukemic cells, the so-called graft-versus-leukemia
(GVL) effect. A major complication of transplantation with bone
marrow from a genetically nonidentical individual is
graft-versus-host-disease (GVHD), whereby the immune cells that
develop from the transplanted bone marrow attack the patient's
tissues and organs. A team of researchers, led by Takanori Teshima,
at Kyushu University Graduate School of Science, Japan, has now
characterized more precisely the cellular responses underlying GVL
and GVDH in mice. The data suggest that immune cells that attack
the tissues of a transplant recipient become dysfunctional and that
this leads to a decrease in GVL activity. Furthermore, blocking the
protein on the tissues of mouse transplant recipients responsible
for driving immune cell dysfunction (PD-1) improved GVL activity.
The authors conclude that there are cellular processes that
distinguish GVL activity from that underlying GVDH and suggest that
their data point to potential approaches to improving the efficacy
of bone marrow transplantation.
TITLE: Alloantigen expression on non-hematopoietic cells reduces
graft-versus-leukemia effects in mice
AUTHOR CONTACT:
Takanori Teshima
Kyushu University Graduate School of Science, Fukuoka, Japan.
Phone: 81.92.642.5947; Fax: 81.92.642.5951; E-mail:
tteshima@cancer.med.kyushu-u.ac.jp.
View this article at:
http://www.jci.org/articles/view/39165?key=7ed15255d23e2f9306a6
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