Prostaglandin E₂ metabolism is activated in Schwann cell lines derived from human NF1 malignant peripheral nerve sheath tumors

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are characteristic of Neurofibromatosis type 1 (NF1), a human genetic disorder affecting approximately 1 in 3000 individuals. The absence of neurofibromin in Schwann cells results in hyperactivation of Ras, which contributes to Schwann cell hyperplasia. However, additional intracellular abnormalities in Schwann cells might contribute to the malignancy. We now report that cell lines derived from MPNSTs secrete elevated levels of prostaglandin E(2) (PGE(2)), express higher levels of phosphorylated mitogen-activated protein kinase (MAPK), phosphorylated cytosolic phospholipaseA(2) (cPLA(2)) and cyclooxygenase 2 (COX-2) when compared to normal adult human Schwann cells (nhSCs). PCR analysis reveals that NF1 MPNST cell lines express mRNA for both EP2 and EP4 prostaglandin E2 receptors, whereas nhSCs express only the EP4 receptor. COX-2 inhibitors and PGE(2) receptor antagonists decrease the proliferation of MPNST cell lines. These results indicate that prostaglandin metabolism is activated in MPNSTs and might contribute to tumor growth in NF1.

Aberrant cAMP Metabolism in NF1 Malignant Peripheral Nerve Sheath Tumor Cells

“…They are both coupled with the cAMP metabolism in numerous cell types [28]. The additional presence of the EP2 receptor on NF1 MPNST cells coupled with the secretion of PGE 2 [17] may be responsible for the increased cAMP level compared to the cAMP level in normal human adult Schwann cells only expressing the EP4 receptor and expressing much lower amounts of PGE 2 .…”

“…Other upstream effectors of cAMP metabolism such as prostaglandin metabolism may also affect cAMP levels. We have previously reported that both NF1 tumors and MPNST cell lines express elevated levels of prostaglandin PGE 2 and express higher levels of COX2 relative to normal human Schwann cells [17]. It is well known that increased prostaglandin metabolism [18,19] and defects in the cAMP pathway [20] are major contributors to malignant transformation.…”

Neurofibromatosis Type I: From Genetic Mutation to Tumor Formation

“…MPNST Schwann cell lines also secrete more PGE 2 than normal human Schwann cells, and the PGE-inducible synthetic enzyme COX-2 is expressed by MPNST cell lines but not by normal Schwann cells. Furthermore, treatment of the cell lines with PGE 2 receptor antagonists resulted in a decrease in cell proliferation (Deadwyler et al, 2004).…”

“…The prostaglandin E 2 (PGE 2 ) receptor EP2 is expressed by MPNST cell lines but not by normal human Schwann cells (Deadwyler et al, 2004). MPNST Schwann cell lines also secrete more PGE 2 than normal human Schwann cells, and the PGE-inducible synthetic enzyme COX-2 is expressed by MPNST cell lines but not by normal Schwann cells.…”

A Career Perspective on the Discipline of Neurochemistry

“…At this point in my career, a genetics graduate student (Karen Klein) joined my lab with a passion to study Schwann cells in the context of disease, particularly neurofibromatosis (a disease in which Schwann cells proliferate abnormally and form tumors) (see [71] for a recent review). As a result, we began a 15 year investigation by my lab into the signal transduction abnormalities which resulted in tumor formation by these aberrant Schwann cells [34,[47][48][49][72][73][74][75][76][77]. These studies could easily be classified as strictly neurochemical, but the pendulum was swinging toward more holistic and applied research with less emphasis on molecular and descriptive studies.…”