The Impact of Olive Oil Compounds on the Metabolic Reprogramming of Cutaneous Melanoma Cell Models.

Cheila Brito,Marta Pojo,Ana Tomás,Maria Rosário Bronze,Sandra Silva,Ana Teresa Serra

doi:10.3390/molecules26020289

Abstract

Cutaneous melanoma is the deadliest type of skin cancer, characterized by a high molecular and metabolic heterogeneity which contributes to therapy resistance. Despite advances in treatment, more efficient therapies are needed. Olive oil compounds have been described as having anti-cancer properties. Here, we clarified the cytotoxic potential of oleic acid, homovanillyl alcohol, and hydroxytyrosol on melanoma cells. Metabolic viability was determined 48 h post treatment of A375 and MNT1 cells. Metabolic gene expression was assessed by qRT-PCR and Mitogen-Activated Protein Kinase (MAPK) activation by Western blot. Hydroxytyrosol treatment (100 and 200 µM) significantly reduced A375 cell viability (p = 0.0249; p < 0.0001) which, based on the expression analysis performed, is more compatible with a predominant glycolytic profile and c-Jun N-terminal kinase (JNK) activation. By contrast, hydroxytyrosol had no effect on MNT1 cell viability, which demonstrates an enhanced oxidative metabolism and extracellular signal-regulated kinase (ERK) activation. This compound triggered cell detoxification and the use of alternative energy sources in A375 cells, inhibiting JNK and ERK pathways. Despite oleic acid and homovanillyl alcohol demonstrating no effect on melanoma cell viability, they influenced the MNT1 glycolytic rate and A375 detoxification mechanisms, respectively. Both compounds suppressed ERK activation in MNT1 cells. The distinct cell responses to olive oil compounds depend on the metabolic and molecular mechanisms preferentially activated. Hydroxytyrosol may have a cytotoxic potential in melanoma cells with predominant glycolytic metabolism and JNK activation.

Highlights

Cutaneous melanoma (CM) arises from the malignant transformation of melanocytes found in the skin [1]
This study demonstrates that melanoma cells have a distinct response to natural olive oil compounds, which could be explained by a considerable metabolic and molecular heterogeneity
We showed that oleic acid and homovanillyl alcohol are likely not a reliable therapeutic strategy in melanoma by themselves, because these compounds may facilitate the activation of compensatory mechanisms which increase cell detoxification and/or the dependence on an oxidative metabolism, essential for melanoma cells to resist to stress conditions

Summary

Introduction

Cutaneous melanoma (CM) arises from the malignant transformation of melanocytes found in the skin [1]. Melanoma progression and metastasis are influenced by the molecular and metabolic heterogeneity of melanoma cells, crucial in survival and acquisition of different nutrient sources [5]. This heterogeneity is thought to play an active role in the development of therapy resistance, allowing melanoma cells to change and respond to microenvironmental cues [5]. It represents one of the main barriers to the efficiency of therapeutic approaches [6]. In the case of V-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanomas, highly selective BRAF and mitogenactivated protein kinase (MEK) inhibitors have shown to improve patient survival [7,8,9]

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