HtrA1 protein contributes to the development of resistance to chemotherapy in ovarian and gastric cancers
While many cancer patients initially have a favorable response to chemotherapy for the treatment of solid tumors, resistance to treatment often develops. Resistance can be caused by many factors, including metabolism of the drug, a decrease in drug accumulation in tumor cells, altered expression of molecules involved in cell death, or further DNA mutation or modification that makes the drug ineffective. In a study appearing online on June 8 in advance of print publication in the July issue of the Journal of Clinical Investigation, Viji Shridhar and colleagues from the Mayo Clinic College of Medicine show that 2 antitumor agents, cisplatin and paclitaxel, increase the expression of the protein HtrA1 in ovarian carcinoma cells, which induces cell death. Conversely, reduced HtrA1 expression reduced the effectiveness of cisplatin and paclitaxel.
The authors went on to test whether the level of HtrA1 expression could predict the response to chemotherapy of patients with ovarian or gastric cancer receiving cisplatin-based chemotherapy. The authors found that patients with ovarian or gastric tumors expressing higher levels of HtrA1 showed a better response to chemotherapy compared to those with lower levels of HtrA1 expression. The study reveals a novel pathway by which HtrA1 mediates the ability of chemotherapeutic agents to kill cancer cells, and suggests that loss of HtrA1 in ovarian and gastric cancer may contribute to the development of resistance to chemotherapy.
TITLE: Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity
AUTHOR CONTACT:
Elizabeth Zimmermann
Communications, Mayo Clinic Cancer Center, Rochester, Minnesota, USA.
Phone: (507) 284-5005; E-mail: newsbureau@mayo.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27698
METABOLIC DISEASE
A matter of fat: ghrelin hormone promotes storage of energy as fat
The hormone ghrelin is produced at high levels in the stomach when we are hungry and at decreased levels after meals. As such, this hormone plays a critical role in signaling the brain when we are hungry or full and has become an important focus of obesity research. In a study appearing online on June 8 in advance of print publication in the July issue of the Journal of Clinical Investigation, Francoise Rohner-Jeanrenaud and colleagues from Centre Medical University, Geneva, show that signaling networks in the brain involving ghrelin not only promote food intake but also directly regulate the processing of nutrients by adipose cells. The authors showed that ghrelin administration into the brain of rats may "prime" adipose tissue to store energy as fat by altering the expression of genes that code for adipocyte enzymes involved in nutrient metabolism. The authors suggest that, with further research, drugs that interact with these enzymes and their receptors may be of potential therapeutic value in obesity.
TITLE: Ghrelin action in the brain controls adipocyte metabolism
AUTHOR CONTACT:
Francoise Rohner-Jeanrenaud
Centre Medical University, Geneva, Switzerland.
Phone: 41-22-379-54-36; Fax: 41-22-379-52-60; E-mail: Francoise.Jeanrenaud@medecine.unige.ch.
View the PDF of this article at: https://www.the-jci.org/article.php?id=25811
CARDIOLOGY
Selective enzyme interaction contributes to cardiac hypertrophy
Nucleosomes package DNA into chromosomes inside the cell nucleus and help control gene expression. Enzymes known as Class IIa histone deacetylases (HDACs) cause histone deacetylation, which constricts the nucleosome and represses gene activation. Many enzymes known as serine/threonine kinases control where HDACs are localized inside the cell, but whether certain Class IIa HDACs respond selectively to specific kinases had not been previously determined. In a study appearing online on June 8 in advance of print publication in the July issue of the Journal of Clinical Investigation, Eric Olson and colleagues from the University of Texas Southwestern Medical Center show that the enzyme calcium/calmodulin-dependent kinase II (CaMKII) signals specifically to HDAC4 by binding to a unique docking site on this enzyme that is absent in other class II HDACs. CaMKII-mediated phosphorylation of HDAC4 promotes the export of HDAC4 out of the cell nucleus, and prevents its entry into the nucleus, thereby lifting the HDAC-mediated repression of specific genes. The authors go on to show that CaMKII-mediated phosphorylation of HDAC4 in cardiac cells results in cardiomyocyte enlargement. The study provides new insight into CaMKII and HDAC signaling pathways in the regulation of cardiac growth.
TITLE: CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy
AUTHOR CONTACT:
Eric N. Olson
University of Texas Southwestern Medical Center, Dallas, Texas.
Phone: (214) 648-1187; Fax: (214) 648-1196; E-mail: eric.olson@utsouthwestern.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27438
ONCOLOGY
SMAD4 and PTEN play key roles in liver cancer initiation
Cholangiocellular carcinoma (CC) is the second most common type of primary liver cancer and is associated with a poor prognosis. It has been previously demonstrated that CCs possess alterations of a number of tumor-suppressor genes and oncogenes, however the key events that induce tumor formation have remained unclear. In a study appearing online on June 8 in advance of print publication in the July issue of the Journal of Clinical Investigation, Chu-Xia Deng and colleagues from the NIH, generated a line of mice that develop CC by specifically disrupting expression of the tumor suppressor genes SMAD4 and PTEN in the livers of these mice. Tumors formed in the bile ducts of these animals by 4–7 months of age. The authors show that SMAD4 and PTEN regulate each others' activity in order to balance their expression and repress CC formation. The authors also examined human CC specimens and found that PTEN was inactivated in the majority of cases, and SMAD4 expression was lost in about half of the tumors examined. The results of this study help us understand the relationship between SMAD4 and PTEN and extend our understanding of CC formation.
TITLE: Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten mice
AUTHOR CONTACT:
Chu-Xia Deng
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 402-7225; Fax: (301) 480-1135; E-mail: chuxiad@bdg10.niddk.nih.gov.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27282
IMMUNOLOGY
T cell activity during the immune response: what regulates the regulators?
Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress activation of the immune system and in doing so help prevent aggressive immune responses against our own tissues. However little is known about how Tregs themselves are regulated. In a study appearing online on June 8 in advance of print publication in the July issue of the Journal of Clinical Investigation, Irun R. Cohen and colleagues from the Weizmann Institute of Science in Rehovot, Israel, report that human heat shock protein 60 (HSP6) stimulates human Tregs. They show that administration of HSP60, or a peptide thereof, to cultures of human T cells significantly enhanced the ability of relatively low concentrations of Tregs to downregulate the activity of other T cells. They found that this involves signaling via Toll-like receptor 2 (TLR2). The results of this study provide important new insights into Treg signaling and how Tregs affect the immune function of regulated T cells. Clinically, the upregulation of Treg function has important implications for the control of autoimmune diseases and other inflammatory diseases such as lupus and rheumatoid arthritis.
TITLE: Heat shock protein 60 enhances CD4+CD25+ regulatory T cell function via innate TLR2 signaling
AUTHOR CONTACT:
Irun R. Cohen
Weizmann Institute of Science, Rehovot, Israel.
Phone and Fax: 972-8-934-2911; E-mail: irun.cohen@weizmann.ac.il.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28423
Journal
Journal of Clinical Investigation