EDITOR'S PICK: Extending the life of an appetite-suppressing peptide
The peptide alpha-MSH works in a region of the brain known as the hypothalamus to suppress appetite. A team of researchers, at Yale University School of Medicine, New Haven, and the University of California Davis, has provided new insight into the way in which levels of the active form of alpha-MSH are regulated in mice. Specifically, genetic and biochemical analysis performed by the team, led by Sabrina Diano and Craig Warden, indicated that the protein PRCP is expressed in the hypothalamus and breaks down the active form of alpha-MSH, generating a slightly smaller peptide that does not suppress food intake. Importantly, administration of PRCP inhibitors to both normal and obese mice reduced their food intake. Further, mice lacking PRCP had increased levels of the active form of alpha-MSH in the hypothalamus and were leaner and shorter than normal mice; they also did not get obese when fed a high-fat diet. The authors suggest that these data are the first step in identifying PRCP as a candidate drug target for the treatment of obesity and obesity-related disorders. Although Richard Palmiter, at the University of Washington, Seattle, also raises this intriguing possibility, he cautions that any drug would need to penetrate the brain.
TITLE: Prolylcarboxypeptidase regulates food intake by inactivating alpha-MSH in rodents
AUTHOR CONTACT:
Sabrina Diano
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: (203) 737-1216; Fax: (203) 785-4747; E-mail: sabrina.diano@yale.edu.
Craig H. Warden
University of California Davis, Davis, California, USA.
Phone: (530) 752-4187; Fax: (530) 752-3516; E-mail: chwarden@ucdavis.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37209
ACCOMPANYING COMMENTARY
TITLE: Reduced levels of neurotransmitter-degrading enzyme PRCP promote obesity
AUTHOR CONTACT:
Richard D. Palmiter
University of Washington, Seattle, Washington, USA.
Phone: (206) 543-6064; Fax: (206) 543-0858; E-mail: palmiter@u.washington.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=40001
EDITOR'S PICK: New breast cancer–promoting gene identified
A team of researchers, at the Genome Institute of Singapore, has identified a new gene that seems to contribute to aggressive breast cancer behavior. As discussed in an accompanying commentary, by Gordon Mills and colleagues, the data generated in this study provide new insight into cellular processes underlying tumor cell proliferation and metastasis and identify potential new therapeutic targets.
In the study, a new informatics approach was used to analyze microarray expression profiles of primary human breast cancers and the gene RCP was identified as a potential breast cancer–promoting gene. Importantly, this gene is found in a region of the genome frequently amplified in human breast cancer. In vitro analysis indicated that overexpression of RCP protein in normal human breast epithelial cells caused them to acquire tumor cell characteristics and function. Conversely, decreasing expression of RCP protein in human breast cancer cell lines reduced their in vitro tumor cell characteristics and in vivo ability to form tumors and metastasize when transplanted into immunodeficient mice. Further analysis identified some of the molecules affected by RCP overexpression, including the known tumor-promoting protein RAS. These data led the authors to suggest that one mechanism by which RCP promotes breast cancer is likely to be through activation of the RAS signaling pathway and that targeting RCP might provide a way to therapeutically inhibit this known tumor-promoting pathway.
TITLE: RCP is a human breast cancer–promoting gene with Ras-activating function
AUTHOR CONTACT:
Lance David Miller
Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Phone: (336) 716-6017; Fax: (336) 716-0255; E-mail: ldmiller@wfubmc.edu.
Bing Lim
Genome Institute of Singapore, Singapore, Singapore.
Phone: 65-6478-8156; Fax: 65-6478-9005; E-mail: limb1@gis.a-star.edu.sg.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37622
ACCOMPANYING COMMENTARY
TITLE: Genomic amplicons target vesicle recycling in breast cancer
AUTHOR CONTACT:
Gordon B. Mills
University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: (713) 563-4200; Fax: (713) 563-4235; E-mail: gmills@mdanderson.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=40256
TUMOR IMMUNOLOGY: Killing off human tumor cells
The proteins RIG-I and MDA-5 are important intracellular sensors of viruses (specifically they detect viral RNA), triggering an antiviral immune response. Robert Besch and colleagues, at Ludwig Maximilian University, Germany, have now identified a new function downstream of RIG-I and MDA-5 activation: they can trigger a signaling pathway that leads to a cell death process known as apoptosis. The authors hope that this function can be harnessed to generate an efficient anticancer therapeutic.
A key result in the study indicated that although synthetic molecules that mimic viral RNA and bind RIG-I and MDA-5 triggered the apoptotic cell death pathway in vitro in both human skin cancer cells (specifically cells of the most aggressive form of skin cancer, melanoma) and noncancerous cells, the noncancerous cells were much less sensitive to apoptotic cell death than the melanoma cells. Further, administration of molecules that bind RIG-I and MDA-5 to immunodeficient mice injected with a human melanoma cell line dramatically reduced spreading of the tumor to the lungs, due to apoptotic tumor cell death. The authors therefore suggest that synthetic molecules that bind RIG-I and MDA-5 might have anticancer therapeutic potential due to their ability to trigger tumor cell death by apoptosis. They further suggest that such molecules would also be likely to stimulate antitumor immune responses, further boosting their anticancer effects. In an accompanying commentary, Laurence Zitvogel and Guido Kroemer discuss in more detail the potential for synthetic molecules that bind RIG-I and MDA-5 to elicit synergistic anticancer effects.
TITLE: Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon–independent apoptosis in human melanoma cells
AUTHOR CONTACT:
Robert Besch
Ludwig Maximilian University, Munich, Germany.
Phone: 49-89-5160-6365; Fax: 49-89-5160-6202; E-mail: robert.besch@med.uni-muenchen.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37155
ACCOMPANYING COMMENTARY
TITLE: Anticancer immunochemotherapy using adjuvants with direct cytotoxic effects
AUTHOR CONTACT:
Guido Kroemer
INSERM U848, Institut Gustave Roussy, Villejuif, France.
Phone: 33-1-42-11-60-46; Fax: 33-1-42-11-60-47; E-mail: kroemer@igr.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39991
HEMATOLOGY: Mopping up hemoglobin stops it constricting blood vessels
Some medical conditions, such as hemolytic anemia, sickle cell disease, and severe malaria, are characterized by the destruction of red blood cells. Many of the severe, often life-threatening, symptoms of these diseases are caused by the large amounts of the molecule hemoglobin (Hb) that are released into the blood upon red blood cell destruction; in particular, the ability of Hb to cause blood vessel constriction. There are currently no treatments to target Hb released into the blood. However, a team of researchers, at University Hospital, Switzerland, and the US FDA, Bethesda, has found that inducing expression of the molecule haptoglobin in dogs and administering haptoglobin to guinea pigs reduced the effects of Hb on blood vessel constriction and thereby reduced the severe symptoms caused by large amounts of Hb in the blood. Interestingly, the team, led by Dominik Schaer and Abdu Alayash, induced haptoglobin expression in the dogs by injecting them with the drug prednisone, a glucocorticoid used in the clinic to decrease inflammation. The authors hope that these observations can be translated into potential therapies for diseases associated with red blood cell destruction. In an accompanying commentary, Gregory Kato, at the NIH, Bethesda, suggests that these data might help explain the observation that in double-blind, randomized, placebo-controlled trials glucocorticoids were found to initially reduce some of the symptoms of sickle cell disease.
TITLE: Sequestration of extracellular hemoglobin within a haptoglobin complex decreases its hypertensive and oxidative effects in dogs and guinea pigs
AUTHOR CONTACT:
Dominik J. Schaer
University Hospital, Zurich, Switzerland.
Phone: 41-44-255-1111; Fax: 41-44-364-5339; E-mail: dominik.schaer@usz.ch.
Abdu I. Alayash
US FDA, Bethesda, Maryland, USA.
Phone: (301) 827-3813; Fax: (301) 435-4034; E-mail: abdu.alayash@fda.hhs.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=39115
ACCOMPANYING COMMENTARY
TITLE: Haptoglobin halts hemoglobin's havoc
AUTHOR CONTACT:
Gregory J. Kato
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 451-8497; Fax: (301) 451-7091; Email: gkato@nhlbi.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=40258
ONCOLOGY: MicroRNAs block tumor growth
MicroRNAs are short, noncoding RNAs that regulate many cellular and developmental events by extinguishing the expression of a plethora of genes. Many microRNAs are downregulated in tumors. Data generated by Carola Ponzetto and colleagues, at the University of Torino, Italy, in xenotransplant models of rhabdomyosarcoma (RMS), a cancer that arises from skeletal muscle progenitors, indicates that reexpression of muscle-specific microRNAs can block tumor growth. Prasun J. Mishra and Glenn Merlino, at the National Cancer Institute, Bethesda, discuss in more detail the clinical promise and pitfalls of microRNA reexpression therapy in an accompanying commentary.
In the study, the muscle-specific mircoRNAs miR-1 and miR-206 were barely detectable in tumor tissue from individuals with either form of RMS. Importantly reexpression of miR-206 in RMS cells promoted them to take on characteristics of mature skeletal muscle cells in vitro. Furthermore, it blocked tumor growth in xenografted mice and this was associated with the tumor cells gaining expression of genes active in mature skeletal muscle cells. Further analysis revealed one potential molecular mechanism underlying the anticancer effects of miR-206: miR-206 reexpression in RMS cells abrogated expression of MET, a known tumor-promoting protein that is overexpressed in RMS. The authors suggest that because microRNAs target many genes they might be more effective anticancer therapeutics than drugs that target a single gene/protein.
TITLE: The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation
AUTHOR CONTACT:
Carola Ponzetto
University of Torino, Torino, Italy.
Phone: 39-011-6707799; Fax: 39-011-6705931; E-mail: carola.ponzetto@unito.it.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38075
ACCOMPANYING COMMENTARY
TITLE: MicroRNA reexpression as differentiation therapy in cancer
AUTHOR CONTACT:
Glenn Merlino
National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 496-4270; Fax: (301) 480-7618; E-mail: gmerlino@helix.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=40107
HEMATOLOGY: Monoclonal antibodies trigger lysosome-dependent lymphoma/leukemia cell death
The drug rituximab has greatly improved survival in patients with any one of several forms of lymphoma and leukemia involving B cells. Despite this success, a significant proportion of patients ultimately relapse with a lymphoma/leukemia that is resistant to rituximab treatment, indicating the need for new therapeutics. In this context, drugs related to rituximab but with an increased ability to eradicate lymphoma/leukemia cells in mouse models might be clinically useful. Mark Cragg and colleagues, at Southampton University School of Medicine, United Kingdom, have now identified the mechanism by which these rituximab-related therapeutics, which are known as type II monoclonal antibodies (mAbs), elicit their increased efficacy.
Rituximab is a monoclonal antibody that targets the protein CD20, which is specifically expressed on the surface of B cells. It has been previously classified as a type I mAb because it does not directly trigger B cell lymphoma cell death; type II mAbs directly trigger cell death. In this study, the authors have determined how the type II mAb tositumomab, which targets CD20, directly triggers human lymphoma cell lines and primary chronic lymphocytic leukemia cells to undergo cell death. Specifically, they found that tositumomab triggered a cytoplasmic cell death pathway that involved cellular compartments known as lysosomes and that initiation of this process was linked to the ability of the type II mAb to induce homotypic CD20 adhesion. Importantly, a second type II mAb, which targets a protein other than CD20 (specifically it targets HLA-DR), also triggered homotypic adhesion and lysosome-dependent cell death. The authors, and Kirsten Grønbæk and Marja Jäättelä, in an accompanying commentary, therefore suggest that because these antibodies and rituximab eradicate lymphoma/leukemia cells by different mechanisms, type II mAbs might be of benefit to individuals with rituximab-resistant disease.
TITLE: Monoclonal antibodies directed to CD20 and HLA-DR can elicit homotypic adhesion followed by lysosome-mediated cell death in human lymphoma and leukemia cells
AUTHOR CONTACT:
Mark S. Cragg
Southampton University School of Medicine, General Hospital, Southampton, United Kingdom.
Phone: 44-23-80777222 ext. 8056; Fax: 44-23-80704-061; E-mail: msc@soton.ac.uk.
MEDIA CONTACT:
Jill Brown
Association for International Cancer Research, Madras House, St. Andrews, Fife, Scotland, KY16 9EH, United Kingdom.
Phone: 44-7786-927203 or 44-1360-311501; E-mail: jill@jillbrownmedia.co.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37884
ACCOMPANYING COMMENTARY
TITLE: Engaging the lysosomal compartment to combat B cell malignancies
AUTHOR CONTACT:
Marja Jäättelä
Institute for Cancer Biology, Danish Cancer Society, Copenhagen, Denmark.
Phone: 45-35257318; Fax: 45-35257721; E-mail: mj@cancer.dk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=40259
IMMUNOLOGY: The protein EBAG9 keeps cytotoxic immune cells in check
CTLs are immune cells that have a central role in killing virus-infected cells and tumor cells. They execute this function by secreting cytotoxic agents from intracellular compartments known as lytic granules. New insight into the tight regulation of this cytotoxic process has now been provided by Armin Rehm, Uta E. Höpken, and colleagues, at the Max-Delbrück-Center for Molecular Medicine, Germany, who have identified the protein EBAG9 as a negative regulator of mouse CTL cytotoxicity.
In the study, CTLs from mice lacking EBAG9 were found to have increased cytotoxicity in vitro and in vivo. This was associated with increased CTL secretion of granzyme A, a characteristic constituent of lytic granules. Further analysis indicated that EBAG9 has a role in regulating the formation of lytic granules and that in its absence cytotoxic agents are more efficiently sorted into these granules. In an accompanying commentary, Geneviève de Saint Basile and Gaël Ménasché, at INSERM U768, France, highlight the importance of this work and suggest future studies to define more precisely the molecular stage of lytic granule formation controlled by EBAG9.
TITLE: The tumor-associated antigen EBAG9 negatively regulates the cytolytic capacity of mouse CD8+ T cells
AUTHOR CONTACT:
Armin Rehm
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Phone: 49-30-94063229; Fax: 49-30-94063124; E-mail: arehm@mdc-berlin.de
Uta E. Höpken
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Phone: 49-30-94063330; Fax: 49-30-94063124; E-mail: uhoepken@mdc-berlin.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37760
ACCOMPANYING COMMENTARY
TITLE: EBAG9 tempers lymphocyte killing activity
AUTHOR CONTACT:
Geneviève de Saint Basile
INSERM U768, Paris, France.
Phone: 33-1-44-49-50-80; Fax: 33-1-42-73-06-40; E-mail: genevieve.de-saint-basile@inserm.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=40270
HEPATOLOGY: Balancing liver regeneration and injury
In some clinical situations, surgical removal of a massive proportion of the liver or transplantation with a partial liver graft (something known as small-for-size transplantation) is the only option. In both contexts, liver regeneration is crucial to the success of the procedure. One factor linked to impaired liver regeneration is the extent of ischemia-reperfusion injury (IRI), an unavoidable consequence of surgery that occurs when blood reenters the tissues after a period of oxygen deprivation (ischemia). Previous studies have implicated the complement system, a group of blood proteins activated sequentially in inflammatory situations, in both IRI and liver regeneration. In a new study, Stephen Tomlinson and colleagues, at the Medical University of South Carolina, Charleston, have revealed the existence of a balance between complement-dependent injury and regeneration in a combined mouse model of IRI and removal of large portions of the liver. In particular, there was a threshold of complement activation above which it promoted liver regeneration, and this involved the proteins ASP and C5L2. The authors therefore suggest that therapeutic modulation of the complement system might help prevent liver regeneration failure in patients who have had large proportions of their liver removed or undergone small-for-size transplantation.
TITLE: A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice
AUTHOR CONTACT:
Stephen Tomlinson
Medical University of South Carolina, Charleston, South Carolina, USA.
Phone: (843) 792-1450; Fax: (843) 792-2464; E-mail: tomlinss@musc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38289
Journal
Journal of Clinical Investigation