Glutamate increases pancreatic cancer cell invasion and migration via AMPA receptor activation and Kras‐MAPK signaling

Abstract

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.Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies, with exceptionally low survival rates (5-year survival rate less than 5%). 1 Although the cell of origin of PDAC is controversially discussed, 2 pancreatic intraepithelial neoplasias (PanIN) of different grades (1A, 1B, 2, 3) in which increasing numbers of molecular alterations are found (i.e., mutations in the Kras, Smad4 and p53 genes), are believed to belong to the multistep progression model of pancreatic cancer. 3,4 Neurotransmitters and neuropeptides have been shown to play a role in pancreatic carcinogenesis 5-11 and in pancreas-associated diseases 8,[12][13][14][15][16] however, the role of excitatory neurotransmitters and particularly of glutamate in pancreatic cancer is not well defined. Glutamate activates metabotropic receptors (mGluR; G protein-coupled receptors) and the ionotropic (iGluR) receptors N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate 17,18 receptors. AMPA receptors are heteromeric and are assembled from the four subunits GluR1-4 in different combinations. The presence of GluR2 subunit determines AMPA receptor impermeability to Ca 2þ . 17,19,20 Since AMPA receptor activation regulates differentiation, proliferation and migration of embryonic stem cells, [21][22][23][24] it has been hypothesized that modulation of AMPA receptor-mediated signals might be involved in carcinogenesis, particularly because it has also been shown that AMPA signals via the MAPK pathway. [25][26][27] This hypothesis has subsequently been proven for some ...

RETRACTED ARTICLE: MicroRNA-330-3p promotes cell invasion and metastasis in non-small cell lung cancer through GRIA3 by activating MAPK/ERK signaling pathway

“…In this study, western blotting and qRT-PCR demonstrated that GRIA3 level was inversely correlated with miR-330-3p expression. Since AMPAR signaling to KRAS and MAPK pathways, promoted migration and invasion of cells [51], and GRIA3 acted as an important mediator of survival, proliferation, and migration of tumor cell, which, in pancreatic cancer, are regulated by CUX1 downstream of PI3K/AKT [52], we investigated the MAPK/ERK and PI3K/AKT signaling pathways in the migration and invasion of NSCLC cells. Our results revealed that miR-330-3p over-expression increased p-ERK in both H460 and H1975 cells; however, when MEK1/2 was inhibited with U0126, a selective inhibitor, in H460 and H1975 cells, miR-330-3p over-expression decreased the expression of GRIA3.…”

FOXO/TXNIP pathway is involved in the suppression of hepatocellular carcinoma growth by glutamate antagonist MK-801

“…In cancer cells, glutamate signaling pathways are dysregulated and glutamate is released from cancer cells, stimulating cell growth [8,9]. In pancreatic cancer, glutamate stimulates cell invasion and migration [10]. …”

How does cancer cell metabolism affect tumor migration and invasion?

“…75 Glutamate was also observed to increase the invasion and migration of pancreatic cancer cells via AMPA receptor activation and kRas-MAPK signaling. 76 On the other hand, glutamate antagonists decreased motility and invasive activities of adenocarcinoma and breast and lung carcinoma cells. 77 Glutamine taken up through SLC1A5 glutamine transporter was rapidly exported in exchange for essential amino acids, 78 which can activate the mammalian target of rapamycin complex 1 (mTORC1) activity.…”