New target to enhance anticancer drug sensitivity found in translation
The development of resistance to anticancer chemotherapeutic agents remains a large problem. In some cases, such resistance is associated with altered control of a cellular process known as translation, which is central to the generation of proteins. New data, generated by Jerry Pelletier and colleagues, at McGill University, Montreal, have identified a drug that can enhance the sensitivity of mouse cancer cells to standard anticancer chemotherapeutic agents.
In the study, small molecules were screened for their ability to inhibit the initiation of translation by modifying the function of a protein known as eIF4A, which has a central role in translation initiation. A class of natural drugs known as cyclopenta[b]benzofuran flavaglines were found to have the desired effects and one member of this class of compounds was shown to reverse the resistance of cancer cells to anticancer chemotherapeutic agents in a mouse model of lymphoma. The authors therefore suggest that developing approaches to inhibit translation initiation by targeting eIF4A might provide a way to altering drug resistance in cancers exhibiting altered control of translation initiation.
TITLE: Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model
AUTHOR CONTACT:
Jerry Pelletier
McGill University, Montreal, Quebec, Canada.
View the PDF of this article at: https://the-jci/article.php?id=34753
Tumor cells want no contact with immune cells
As tumors progress they develop ways to escape recognition and attack by cells of the immune system. However, the mechanisms by which tumors modify the immune system have not been clearly determined. New insight into the way in which chronic lymphocytic leukemia (CLL) cells limit immune cell attack has now been provided by John Gribben and colleagues, at Barts and The London School of Medicine, United Kingdom.
For immune cells known as CD4+ and CD8+ T cells to become activated they must contact other cells known as APCs. The area of contact is known as the immunological synapse and it is highly organized. In the study, CD4+ and CD8+ T cells from patients with CLL were found to exhibit defective immunological synapse formation with APCs. Further, if CD4+ and CD8+ T cells from healthy individuals were cultured with CLL APCs, they also showed defective immunological synapse formation. As treatment with an immune system-modifying drug improved immunological synapse formation, the authors suggest that approaches to overcoming immunological synapse defects might improve the efficacy of new ways to treat cancer that are currently being developed and that are based on enhancing the antitumor activity of CD4+ and CD8+ T cells.
TITLE: Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug
AUTHOR CONTACT:
John G. Gribben
Barts and The London School of Medicine, London, United Kingdom.
View the PDF of this article at: https://the-jci/article.php?id=35017
How bone growth can be stunted in mice
Hiroshi Kawaguchi and colleagues, at the University of Tokyo, Japan, have provided new insight into the molecules that control the growth of the mouse skeleton.
Mice lacking a protein known as cGKII are dramatically smaller than mice expressing normal levels of this protein, because the bones of their legs and body are much shorter. In the study, it was found that the shorter bones were a result of a defect in bone growth, specifically in a process known as chondrocyte hypertrophy. Further analysis showed that in normal mouse chondrocytes, cGKII inhibited the function of a protein known as GSK-3-beta and that this was important for enhancing chondrocyte hypertrophy. In addition, the bone defects in mice lacking cGKII were partially rescued if the mice were engineered to express reduced levels of GSK-3-beta. These data indicate an important role for cGKII inhibition of GSK-3-beta function in skeletal growth and the authors are now investigating ways in which this information can be used to develop new therapeutics for skeletal disorders that result in dwarfism.
TITLE: Phosphorylation of GSK-3-beta by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes
AUTHOR CONTACT:
Hiroshi Kawaguchi
University of Tokyo, Tokyo, Japan.
View the PDF of this article at: https://the-jci/article.php?id=35243
FABP molecules help link inflammation to obesity-related metabolic diseases
Individuals who are obese are predisposed to a variety of metabolic conditions, including type 2 diabetes. A characteristic of the fat tissue (adipose tissue) of individuals who are obese is that it is inflammed, and understanding the relationship between such inflammation and the onset of the metabolic conditions is of importance in combating what has become a large public health problem. In a new mouse study, Gökhan Hotamisligil and colleagues, at the Harvard School of Public Health, Boston, found that interactions between adipocytes (fat cells) and inflammatory cells called macrophages seem to underlie the inflammation-related metabolic deterioration associated with obesity.
In the study, when adipocytes isolated from mice lacking proteins known as FABPs, which are molecules that govern metabolic and inflammatory responses, were cultured with normal macrophages, the macrophages expressed reduced levels of inflammatory molecules. Likewise, when macrophages isolated from mice lacking FABPs were cultured with normal adipocyes, the adipocytes responded more to insulin and took up more glucose. Similar results, indicating that FABPs from both adipocytes and macrophages contribute to the inflammatory basis for metabolic deterioration, were obtained in vivo. The authors therefore suggest that this FABP-related pathway may be a novel target for metabolism-related disorders.
TITLE: Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice
AUTHOR CONTACT:
Gökhan S. Hotamisligil
Harvard School of Public Health, Boston, Massachusetts, USA.
View the PDF of this article at: https://the-jci/article.php?id=34750
Source: Karen Honey
Journal of Clinical Investigation
Комментариев нет:
Отправить комментарий