Dataset Information

Melanomas prevent endothelial cell death under restrictive culture conditions by signaling through AKT and p38 MAPK/ ERK-1/2 cascades.

ABSTRACT: Although melanoma progression and staging is clinically well characterized, a large variation is observed in pathogenesis, progression, and therapeutic responses. Clearly, intrinsic characteristics of melanoma cells contribute to this variety. An important factor, in both progression of the disease and response to therapy, is the tumor-associated vasculature. We postulate that melanoma cells communicate with endothelial cells (ECs) in order to establish a functional and supportive blood supply. We investigated the angiogenic potential of human melanoma cell lines by monitoring the survival of ECs upon exposure to melanoma conditioned medium (CM), under restrictive conditions. We observed long-term (up to 72 h) EC survival under hypoxic conditions upon treatment with all melanoma CMs. No such survival effect was observed with the CM of melanocytes. The CM of pancreatic and breast tumor cell lines did not show a long-term survival effect, suggesting that the survival factor is specific to melanoma cells. Furthermore, all size fractions (up to < 1 kDa) of the melanoma CM induced long-term survival of ECs. The survival effect observed by the < 1 kDa fraction excludes known pro-angiogenic factors. Heat inactivation and enzymatic digestion of the CM did not inactivate the survival factor. Global gene expression and pathway analysis suggest that this effect is mediated in part via the AKT and p38 MAPK/ ERK-1/2 signaling axis. Taken together, these data indicate the production of (a) survival factor/s (< 1 kDa) by melanoma cell lines, which enables long-term survival of ECs and promotes melanoma-induced angiogenesis.

SUBMITTER: Das AM

PROVIDER: S-EPMC5087299 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Melanomas prevent endothelial cell death under restrictive culture conditions by signaling through AKT and p38 MAPK/ ERK-1/2 cascades.

Das Asha M AM Pescatori Mario M Vermeulen Cindy E CE Rens Joost A P JA Seynhaeve Ann L B AL Koning Gerben A GA Eggermont Alexander M M AM Ten Hagen Timo L M TL

Oncoimmunology 20160812 10

Although melanoma progression and staging is clinically well characterized, a large variation is observed in pathogenesis, progression, and therapeutic responses. Clearly, intrinsic characteristics of melanoma cells contribute to this variety. An important factor, in both progression of the disease and response to therapy, is the tumor-associated vasculature. We postulate that melanoma cells communicate with endothelial cells (ECs) in order to establish a functional and supportive blood supply. ...[more]

PMID: 27853641

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Project description:Homocysteine, a metabolite of the methionine cycle has been reported to play a role in neurotoxicity through activation of N-methyl-d-aspartate receptors (NMDAR)-mediated signaling pathway. The proposed mechanisms associated with homocysteine-NMDAR-induced neurotoxicity involve a unique signaling pathway that triggers a crosstalk between extracellular signal-regulated kinase (ERK) and p38 MAPKs, where activation of p38 MAPK is downstream of and dependent on ERK MAPK. However, the molecular basis of the ERK MAPK-mediated p38 MAPK activation is not understood. This study investigates whether ?-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) play a role in facilitating the ERK MAPK-mediated p38 MAPK activation. Using surface biotinylation and immunoblotting approaches we show that treatment with homocysteine leads to a decrease in surface expression of GluA2-AMPAR subunit in neurons, but have no effect on the surface expression of GluA1-AMPAR subunit. Inhibition of NMDAR activation with D-AP5 or ERK MAPK phosphorylation with PD98059 attenuates homocysteine-induced decrease in surface expression of GluA2-AMPAR subunit. The decrease in surface expression of GluA2-AMPAR subunit is associated with p38 MAPK phosphorylation, which is inhibited by 1-napthyl acetyl spermine trihydrochloride (NASPM), a selective antagonist of GluA2-lacking Ca2+ -permeable AMPARs. These results suggest that homocysteine-NMDAR-mediated ERK MAPK phosphorylation leads to a decrease in surface expression of GluA2-AMPAR subunit resulting in Ca2+ influx through the GluA2-lacking Ca2+ -permeable AMPARs and p38 MAPK phosphorylation. Cell death assays further show that inhibition of AMPAR activity with 2,3-dioxo-6-nitro-1,2,3,4,tetrahydrobenzoquinoxaline-7-sulfonamide (NBQX)/6-cyano-7-nitroquinoxaline-2,3, -dione (CNQX) or GluA2-lacking Ca2+ -permeable AMPAR activity with NASPM attenuates homocysteine-induced neurotoxicity. We have identified an important mechanism involved in homocysteine-induced neurotoxicity that highlights the intermediary role of GluA2-lacking Ca2+ -permeable AMPARs in the crosstalk between ERK and p38 MAPKs.

Dataset Information

Melanomas prevent endothelial cell death under restrictive culture conditions by signaling through AKT and p38 MAPK/ ERK-1/2 cascades.

Publications

Melanomas prevent endothelial cell death under restrictive culture conditions by signaling through AKT and p38 MAPK/ ERK-1/2 cascades.

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