The αMSH-Dependent PI3K Pathway Supports Energy Metabolism, via Glucose Uptake, in Melanoma Cells

Abstract

Stimulation of melanocytes and murine melanoma cells with αMSH plus the PI3K inhibitor LY294002 resulted in ROS increase, oxidative DNA damage, and pigment retention. We performed cellular and molecular biology assays (Western blot, FACS, immunofluorescence analysis, scratch assay) on murine and human melanoma cells. Treatment with αMSH plus LY294002 altered cortical actin architecture. Given that cytoskeleton integrity requires energy, we next evaluated ATP levels and we observed a drop in ATP after exposure to αMSH plus LY294002. To evaluate if the αMSH-activated PI3K pathway could modulate energy metabolism, we focused on glucose uptake by analyzing the expression of the Glut-1 glucose translocator. Compared with cells treated with αMSH alone, those exposed to combined treatment showed a reduction of Glut-1 on the plasma membrane. This metabolic alteration was associated with changes in mitochondrial mass. A significant decrease of the cell migratory potential was also observed. We demonstrated that the αMSH-dependent PI3K pathway acts as a regulator of energy metabolism via glucose uptake, influencing the actin cytoskeleton, which is involved in melanosome release and cell motility. Hence, these results could constitute the basis for innovative therapeutical strategies.

A Side-by-Side Comparison of Wildtype and Variant Melanocortin 1 Receptor Signaling with Emphasis on Protection against Oxidative Damage to DNA

“…Likely because of this signaling bias, the behavior of melanoma cells of identical background but harboring different MC1R forms showed subtle but significant differences in relevant biological properties such as proliferation, cell cycle progression, and response to the genotoxic action of oxidative stress. The functional coupling of the variants to other signaling pathways reported to mediate certain MC1R actions, such as the PPARγ pathway [ 22 , 23 ] or the PI3K pathway [ 22 , 24 , 25 ], has not been investigated, and will be further analyzed in subsequent studies.…”

“…However, work from several laboratories has shown that MC1R signaling is pleiotropic, as it involves not only activation of the cAMP pathway, but also of the peroxisome proliferator activated receptor (PPARγ) pathway [ 22 , 23 ], the PI3K pathway [ 22 , 24 , 25 ], and the extracellular signal regulated protein kinases ERK1 and ERK2 [ 26 ]. ERK1/2 signaling is normally initiated by peptide growth factors binding to receptor tyrosine kinases.…”