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Glutamate increases pancreatic cancer cell invasion and migration via AMPA receptor activation and Kras‐MAPK signaling
Author(s) -
Herner Alexander,
Sauliunaite Danguole,
Michalski Christoph W.,
Erkan Mert,
Oliveira Tiago De,
Abiatari Ivane,
Kong Bo,
Esposito Irene,
Friess Helmut,
Kleeff Jörg
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25898
Subject(s) - ampa receptor , pancreatic cancer , cancer research , glutamate receptor , mapk/erk pathway , chemistry , biology , microbiology and biotechnology , receptor , signal transduction , cancer , biochemistry , genetics
Glutamate has been implicated in tumorigenesis through activation of alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors (AMPAR). However, the function of a glutamate‐to‐AMPAR signal in pancreatic ductal adenocarcinoma (PDAC) has remained elusive. We now show that glutamate‐mediated AMPA receptor activation increases invasion and migration of pancreatic cancer cells via activation of the classical MAPK pathway. Glutamate levels were increased in pancreatic cancer accompanied by downregulation of GluR subunits 1, 2, and 4. In pancreatic cancer precursor lesions, pancreatic intraepithelial neoplasia (PanIN), GluR1 subunit levels were strikingly and step‐wise increased but its expression was rare in PDAC. Pharmacological inhibition or RNAi‐mediated suppression of GluR1 or GluR2 did not affect cancer cell growth but significantly decreased invasion. In a K‐ras wildtype cell line, AMPA receptor activation enhanced K‐ras activity and—further downstream—phosphorylation of p38 and of p44/42. Preemptive blockade of AMPA receptors in a mouse model of pancreatic cancer inhibited tumor cell settling. AMPA receptor activation thus not only activates MAPK signalling but also directly increases activity of K‐ras. Glutamate might serve as a molecular switch that decreases the threshold of K‐ras‐induced oncogenic signalling and increases the chance of malignant transformation of pancreatic cancer precursor lesions.