Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation
ABSTRACT Evidence has been accumulated that glioblastoma cells release and exploit glutamate for proliferation and migration by autocrine or paracrine loops through Ca2+-permeable AMPA-type glutamate receptors. Here, we show that Ca2+ signaling mediated by AMPA receptor regulates the growth and motility of glioblastoma cells via activation of Akt. Ca2+ supplied through Ca2+-permeable AMPA receptor phosphorylated Akt at Ser-473, thereby facilitating proliferation and mobility. A dominant-negative form of Akt inhibited cell proliferation and migration accelerated by overexpression of Ca2+-permeable AMPA receptor. In contrast, introduction of a constitutively active form of Akt rescued tumor cells from apoptosis induced by the conversion of Ca2+-permeable AMPA receptor to Ca2+-impermeable receptors by the delivery of GluR2 cDNA. Therefore, Akt functions as downstream effectors for Ca2+-signaling mediated by AMPA receptor in glioblastoma cells. The activation of the glutamate-AMPA receptor-Akt pathway may contribute to the high degree of anaplasia and invasive growth of human glioblastoma. This novel pathway might give an alternative therapeutic target.
SourceAvailable from: Simone Hausmann[Show abstract] [Hide abstract]
ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an extremely poor prognosis. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. In genetically engineered mouse models, induction of pancreatitis accelerates PDAC development, and patients with chronic pancreatitis are known to have a higher risk of developing pancreatic cancer. In recent years, much effort has been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Many inflammatory pathways have been identified and inhibitors have been developed in order to prevent cancer development and progression. In this chapter, we discuss the role of inflammatory pathways in the initiation and progression of pancreatic cancer as well as the role of inhibitors used in treatment and prevention of pancreatic cancer.Advances in Experimental Medicine and Biology 01/2014; 816:129-51. DOI:10.1007/978-3-0348-0837-8_6 · 2.01 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, and has the highest propensity to manifest as metastatic disease. Recent characterizations of the genetic signature of ccRCC have revealed several factors correlated with tumor cell migration and invasion; however the specific events driving malignancy are not well defined. Furthermore, there remains a lack of targeted therapies that result in long-term, sustainable response in patients with metastatic disease. We show here that neuronal pentraxin 2 (NPTX2) is over-expressed specifically in ccRCC primary tumors and metastases, and that it contributes to tumor cell viability and promotes cell migration through its interaction with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR4. We propose NPTX2 as a novel molecular target for therapy for ccRCC patients diagnosed with or at risk of developing metastatic disease.Cancer Research 06/2014; DOI:10.1158/0008-5472.CAN-14-0210 · 9.28 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Malignant gliomas are devastating tumours that frequently kill patients within 1 year of diagnosis. The major obstacle to a cure is diffuse invasion, which enables tumours to escape complete surgical resection and chemo- and radiation therapy. Gliomas use the same tortuous extracellular routes of migration that are travelled by immature neurons and stem cells, frequently using blood vessels as guides. They repurpose ion channels to dynamically adjust their cell volume to accommodate to narrow spaces and breach the blood-brain barrier through disruption of astrocytic endfeet, which envelop blood vessels. The unique biology of glioma invasion provides hitherto unexplored brain-specific therapeutic targets for this devastating disease.Nature reviews. Neuroscience 06/2014; 15(7):455-65. DOI:10.1038/nrn3765 · 31.38 Impact Factor