EDITOR'S PICK: Impaired activity of the protein MTOR a strain on the heart
A team of researchers, led by Gianluigi Condorelli, at the University of California San Diego, La Jolla, has generated data in mice that suggest that drugs that inhibit the protein MTOR, which are used to treat several forms of cancer, might have adverse effects on heart function in patients with ongoing heart dysfunction.
In the study, it was found that adult mice lacking MTOR in their heart muscle cells developed a fatal heart condition. Disease was associated with accumulation of the protein 4E-BP1, which is an inhibitor of protein generation that is normally held in check by a protein complex containing MTOR. Further analysis indicated that in a model of high blood pressure the mice lacking MTOR in their heart muscle cells developed heart failure more quickly than did normal mice. Importantly, deletion of 4E-BP1 under these conditions improved heart function and survival. Thus, decreased MTOR activity impairs the protective heart response to stress, by enhancing 4E-BP1 activity, providing a potential new therapeutic strategy for improving heart function in patients with heart failure and a warning to clinicians using MTOR inhibitors.
TITLE: MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice
AUTHOR CONTACT:
Gianluigi Condorelli
University of California San Diego, La Jolla, California, USA.
Phone: 858.822.5563; Fax: 858.822.3027; E-mail: gcondorelli@ucsd.edu.
View this article at: http://www.jci.org/articles/view/43008?key=9037a905ddcd3c581e01
EDITOR'S PICK: A dead Sirt(3) to protect preimplantation embryos
Infertility affects approximately 10% of couples worldwide. Although assisted reproductive technologies such as in vitro fertilization are commonly used in developed countries to treat infertile couples, the processes remain relatively inefficient. Better understanding of events such as embryo development prior to implantation, a time when many potential natural pregnancies fail, could help improve the efficiency of assisted reproductive technologies. In this context, a team of researchers, led by Hiroki Kurihara, at the University of Tokyo, Japan, has now determined that the protein Sirt3 helps protect preimplantation mouse embryos against stress conditions during in vitro fertilization and culture. Of potential clinical significance, the negative effects of Sirt3 inactivation on mouse embryos could be overcome by culture in the presence of an antioxidant or in low oxygen conditions.
TITLE: Sirt3 protects in vitro–fertilized mouse preimplantation embryos against oxidative stress–induced p53-mediated developmental arrest
AUTHOR CONTACT:
Hiroki Kurihara
Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Phone: 81.3.5841.3498; Fax: 81.3.5684.4958; E-mail: kuri-tky@umin.ac.jp.
View this article at: http://www.jci.org/articles/view/42020?key=4386df088fb2a206cfd0
HEPATOLOGY: Drug clearance uncovered
A team of researchers, led by Alfred Schinkel, at The Netherlands Cancer Institute, The Netherlands, have generated mice that they believe will be of great value for drug development and drug therapy optimization.
Proteins known as OATPs are thought to have an important role in the removal of drugs from the body. Understanding the contribution of different OATPs to the drug removal process is of interest in identifying ways to manipulate drug clearance from the body, for example to increase drug levels in the blood, and in optimizing the development of drugs. To investigate the role of OATPs of the 1A and 1B subfamilies, the team generated mice lacking all established and predicted mouse Oatp1a/1b proteins. Consistent with an important role for these proteins in drug removal from the body, these mice showed increased retention of the drugs methotrexate and fexofenadine in the blood. Thus, these animals will be of use to investigators seeking to understand the pharmacokinetics of the drugs they are developing.
TITLE: Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs
AUTHOR CONTACT:
Alfred H. Schinkel
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Phone: 31.20.5122046; Fax: 31.20.6691383; E-mail: a.schinkel@nki.nl.
View this article at: http://www.jci.org/articles/view/42168?key=abd6f6e9c817e5d4d3d6
ONCOLOGY: Variation is the spice of life for prostate cancer progression
A team of researchers, led by Stephen Plymate, at the University of Washington School of Medicine, Seattle, has identified a mechanism underlying the progression of disease in prostate cancer patients whose disease has stopped responding to therapies that knockdown hormone levels. The authors hope that these data might help identify patients who are likely to suffer from early cancer recurrence and provide a potential new therapeutic target.
Testosterone, acting via the protein AR, is a key driver of prostate cancer. Treatments that reduce testosterone levels are therefore one approach used to treat the disease; however, they often only give temporary relief. Disease progression is associated with increased AR expression and signaling despite low levels of testosterone. Plymate and colleagues outline a mechanistic explanation for this by identifying a new AR variant that they find can contribute to cancer progression in human prostate cancer xenograft models in mice following treatment that decreases testosterone levels. Importantly, this AR variant was detected frequently in human prostate cancer metastases. The authors therefore suggest that looking for AR variants such as this might provide a way to identify patients who are likely to quickly become resistant to hormone therapies.
TITLE: Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant
AUTHOR CONTACT:
Stephen R. Plymate
University of Washington School of Medicine, Seattle, Washington, USA.
Phone: 206.897.5336; Fax: 206.897.5396; E-mail: splymate@u.washington.edu.
View this article at: http://www.jci.org/articles/view/41824?key=e203e22e5795bba27d7c
ONCOLOGY: Giving the green light to cancer cells: an inside look at tumor spread
A leading cause of death for cancer patients is when their cancer spreads to the lung and a secondary tumor develops there. How these secondary lung tumors (lung metastases) progress from a single invading cell to a large metastatic lesion is poorly understood. In an effort to gain a closer look at this process, a team of researchers, led by Chand Khanna, at the National Institutes of Health, Bethesda, have developed a method to label tumor cells with green fluorescent protein and watch these cells grow in cultured mouse lung. Labeling the cells with green fluorescence allowed the investigators to monitor the growth of the tumor cells — and thus model lung metastasis — in real time. Using this model it was possible to faithfully predict the behavior of different cancer cell lines with known metastatic potential. As drugs known to inhibit metastasis development in mouse models of lung metastasis blocked tumor growth in the new model, the authors hope that it will be a useful tool in the pre-clinical evaluation of potential therapeutics.
TITLE: Modeling metastasis biology and therapy in real time in the mouse lung
AUTHOR CONTACT:
Chand Khanna
National Cancer Institute, NIH, Bethesda, Maryland, USA.
Phone: 301.594.3406; Fax: 301.443.1838; E-mail: khannac@mail.nih.gov.
View this article at: http://www.jci.org/articles/view/40252?key=fa575e94e9cca80a0c7e
ONCOLOGY: The protein HIF2-alpha: a therapeutic target in cancer?
Tumors not only contain cancerous cells but also other cell types including immune cells known as tumor-associated macrophages (TAMs). Although the role of TAMs in tumor progression has been controversial, it is known that high levels of expression of the protein HIF2-alpha in TAMs correlates with highly aggressive tumors and poor prognosis. A team of researchers, led by Celeste Simon, at the University of Pennsylvania, Philadelphia, has now determined a reason why expression of HIF2-alpha in TAMs is associated with negative outcomes by studying mice lacking HI2-alpha in immune cells known as myeloid cells, a population that includes TAMs. Specifically, they find that in two mouse models of cancer, the mutant mice exhibit reduced tumor cell proliferation and tumor progression. The authors therefore suggest that HIF2-alpha could be a promising therapeutic target in the fight against cancer.
TITLE: Hypoxia-inducible factor 2 alpha regulates macrophage function in mouse models of acute and tumor inflammation
AUTHOR CONTACT:
M. Celeste Simon
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: 215.746.5532; Fax: 215.746.5511; E-mail: celeste2@mail.med.upenn.edu.
View this article at: http://www.jci.org/articles/view/39506?key=17da10f96a57c9826e36
Journal
Journal of Clinical Investigation