Elevated levels of mitogen-activated protein kinase/extracellular regulatory kinase (MAPK/ERK) activity are frequently found in some cancer cells. In efforts to reduce tumor growth, attempts have been made to develop cancer therapeutic agents targeting the MAPK. Here, by use of biologic, biochemical, and gene manipulation methods in human polymorphonuclear neutrophils (PMNs), we have identified a key pathway important in normal cell function involving MAPK/ERK in PMNs for growth inhibition of Candida albicans. Contact with C albicans triggered MAPK/ERK activation in PMNs within 5 minutes, and blocking of MAPK/ERK activation, either by the pharmacologic reagent PD098059 or by dominant-negative MAPK kinase (MEK) expression via vaccinia viral delivery, suppressed antimicrobial activity. Rac and Cdc42, but not Ras or Rho, were responsible for this MAPK/ERK activation. Expression of dominant-negative Rac (N17Rac) or Cdc42 (N17Cdc42) eliminated not only C albicans- mediated ERK phosphorylation but also phagocytosis and granule migration toward the ingested microbes, whereas dominant-negative Ras (N17Ras) and Rho (N19Rho) did not. PAK1 (p21-activated kinase 1) activation is induced by C albicans, suggesting that PAK1 may also be involved in the Rac1 activation of MAPK/ERK. We conclude from these data that Rac/Cdc42-dependent activation of MAPK/ERK is a critical event in the immediate phagocytic response of PMNs to microbial challenge. Therefore, use of MAPK pharmacologic inhibitors for the treatment of cancer may result in the interruption of normal neutrophil function. A balance between therapeutic outcome and undesirable side effects must be attained to achieve successful and safe anticancer therapy.
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http://dx.doi.org/10.1182/blood-2001-12-0180 | DOI Listing |
Gen Comp Endocrinol
January 2025
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China. Electronic address:
The melanocortin-3 receptor (MC3R) was recognized for its critical role in energy metabolism and inflammatory responses in mammals; however, its functions in fish remain poorly understood. This study characterized the mc3r gene in goldfish, investigating its sequence, tissue distribution, and pharmacological responses. The coding sequence of goldfish mc3r was 975 bp, translating to a 325-amino-acid protein typical of G protein-coupled receptors, with notable conservation across cyprinids.
View Article and Find Full Text PDFStem Cell Reports
December 2024
Laboratorio di Biologia, Scuola Normale Superiore, 56126 Pisa, Italy; Istituto di Biofisica, Consiglio Nazionale delle Ricerche, 56124 Pisa, Italy. Electronic address:
The mechanisms that determine distinct embryonic pallial identities remain elusive. The central role of Wnt signaling in directing dorsal telencephalic progenitors to the isocortex or hippocampus has been elucidated. Here, we show that timely inhibition of MAPK/ERK and BMP signaling in neuralized mouse embryonic stem cells (ESCs) specifies a cell identity characteristic of the allocortex.
View Article and Find Full Text PDFJ Transl Med
December 2024
Gastroenterology Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No.324 JingwuWeiqi Road, Jinan, Shandong, 250021, China.
Background: The overall prognosis of patients with esophageal cancer (EC) is extremely poor. There is an urgent need to develop innovative therapeutic strategies. This study will investigate the anti-cancer effects of exosomes loaded with specific anti-cancer microRNAs in vivo and in vitro.
View Article and Find Full Text PDFCancer Rep (Hoboken)
December 2024
Department of Hematology and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Front Oncol
December 2024
Department of Medical Oncology, International Ward, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, China.
Background: ROS1, a member of the sevenless subfamily of tyrosine kinase insulin receptors, promotes tumor cell survival, proliferation, and metastasis by activating the JAK/STAT, PI3K/AKT, and MAPK/ERK pathways. It only accounts for about 2% of total NSCLC cases. No cases of acquired ROS-1 rearrangement have been reported worldwide.
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