Zeolite 4A, a Synthetic Silicate, Suppresses Melanogenesis through the Degradation of Microphthalmia-Associated Transcription Factor by Extracellular Signal-Regulated Kinase Activation in B16F10 Melanoma Cells

Recent advances in melanoma therapy increased median survival in patients. However, death rates are still high, motivating the need of novel avenues in melanoma treatment. Cold physical plasma expels a cocktail of reactive species that have been suggested for cancer treatment. High species concentrations can be used to exploit apoptotic redox signaling pathways in tumor cells. Moreover, an immune-stimulatory role of plasma treatment, as well as plasma-killed tumor cells, was recently proposed, but studies using primary immune cells are scarce. To this end, we investigated the role of plasma-treated murine B16F10 melanoma cells in modulating murine immune cells’ activation and marker profile. Melanoma cells exposed to plasma showed reduced metabolic and migratory activity, and an increased release of danger signals (ATP, CXCL1). This led to an altered cytokine profile with interleukin-1β (IL-1β) and CCL4 being significantly increased in plasma-treated mono- and co-cultures with immune cells. In T cells, plasma-treated melanoma cells induced extracellular signal-regulated Kinase (ERK) phosphorylation and increased CD28 expression, suggesting their activation. In monocytes, CD115 expression was elevated as a marker for activation. In summary, here we provide proof of concept that plasma-killed tumor cells are recognized immunologically, and that plasma exerts stimulating effects on immune cells alone.

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Role of Acid Sphingomyelinase-Induced Signaling in Melanoma Cells for Hematogenous Tumor Metastasis

Cellular Physiology and Biochemistry ◽

10.1159/000438604 ◽

2016 ◽

Vol 38 (1) ◽

pp. 1-14 ◽

Cited By ~ 11

Author(s):

Alexander Carpinteiro ◽

Nadine Beckmann ◽

Aaron Seitz ◽

Gabriele Hessler ◽

Barbara Wilker ◽

...

Keyword(s):

Tumor Cell ◽

Tumor Cells ◽

Tumor Metastasis ◽

Melanoma Cells ◽

Acid Sphingomyelinase ◽

B16f10 Melanoma ◽

Tumor Cell Adhesion ◽

Activated Platelets ◽

Extracellular Signal ◽

B16f10 Melanoma Cells

Background: Hematogenous metastasis of malignant tumor cells is a multistep process that requires release of tumor cells from the local tumor mass, interaction of the tumor cells with platelets in the blood, and adhesion of either the activated tumor cells or the complexes of platelets and tumor cells to the endothelial cells of the target organ. We have previously shown that the interaction of melanoma cells with platelets results in the release of acid sphingomyelinase (Asm) from activated platelets. Secreted platelet-derived Asm acts on malignant tumor cells to cluster and activate integrins; such clustering and activation are necessary for tumor cell adhesion to endothelial cells and for metastasis. Methods: We examined the response of tumor cells to treatment with extracellular sphingomyelinase or co-incubation with wild-type and Asm-deficient platelets. We determined the phosphorylation and activation of several intracellular signaling molecules, in particular p38 kinase (p38K), phospholipase Cγ (PLCγ), ezrin, and extracellular signal-regulated kinases. Results: Incubation of B16F10 melanoma cells with Asm activates p38 MAP kinase (p38K), phospholipase Cγ (PLCγ), ezrin, and extracellular signal-regulated kinases. Co-incubation of B16F10 melanoma cells with wild-type or Asm-deficient platelets showed that the phosphorylation/activation of p38K is dependent on Asm. Pharmacological blockade of p38K prevents activation of β1 integrin and adhesion in vitro. Most importantly, inhibition of p38K activity in B16F10 melanoma cells prevents tumor cell adhesion and metastasis to the lung in vivo, a finding indicating the importance of p38K for metastasis. Conclusions: Asm, secreted from activated platelets after tumor cell-platelet contact, induces p38K phosphorylation in tumor cells. This in turn stimulates β1 integrin activation that is necessary for adhesion and subsequent metastasis of tumor cells. Thus, inhibition of p38K might be a novel target to prevent tumor metastasis.

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