JCI online early table of contents: June 7, 2024

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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 ligand𔂿 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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