Prognostic implications of markers of the metabolic phenotype in human cutaneous melanoma

Nájera, Laura; Alonso-Juarranz, Miguel; Garrido, M.; Ballestı́n, Claudio; Moya, Laura; Martínez‐Díaz, M.; Carrillo, Rosario; Juarranz, Ángeles; Rojo, Federico; Cuezva, José M.; Rodríguez-Peralto, José L.

doi:10.1111/bjd.17513

Cited by 20 publications

(16 citation statements)

References 51 publications

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“…Despite, tyrosine phosphorylation of glycolytic enzymes usually increases the activities of a majority of glycolytic enzymes, the tyrosine phosphorylation of PKM2 paradoxically results in a decreased PKM2 activity that in turn promotes the Warburg effect [36]. It is possible that the OLEO-driven PKM2 reduction may reduce its glycolytic promotion [37]. PKM2 overexpression was observed in melanoma human samples compared to naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma.…”

Section: Discussionmentioning

confidence: 99%

Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract

Ruzzolini

Peppicelli

Bianchini

et al. 2020

Cancers

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Oleuropein (Ole), the main bioactive phenolic component of Olea europaea L. has recently attracted the scientific attention for its several beneficial properties, including its anticancer effects. This study is intended to investigate whether an olive leaf extract enriched in Ole (OLEO) may counteract the aerobic glycolysis exploited by tumor cells. We found that OLEO decreased melanoma cell proliferation and motility. OLEO was also able to reduce the rate of glycolysis of human melanoma cells without affecting oxidative phosphorylation. This reduction was associated with a significant decrease of glucose transporter-1, protein kinase isoform M2 and monocarboxylate transporter-4 expression, possible drivers of such glycolysis inhibition. Extending the study to other tumor histotypes, we observed that the metabolic effects of OLEO are not confined to melanoma, but also confirmed in colon carcinoma, breast cancer and chronic myeloid leukemia. In conclusion, OLEO represents a natural product effective in reducing the glycolytic metabolism of different tumor types, revealing an extended metabolic inhibitory activity that may be well suited in a complementary anti-cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract

Ruzzolini

Peppicelli

Bianchini

et al. 2020

Cancers

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“…PKM2 plays a crucial role in aerobic glycolysis, which is the predominant metabolic pathway in tumor cells. It correlates with unfavorable survival in hepatocellular carcinoma, melanoma and other tumors [35][36][37]. PKM2 can predict chemotherapy sensitivity in advanced lung cancer patients [38,39].…”

Section: Discussionmentioning

confidence: 99%

High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict worse survival in human lung adenocarcinoma

Long¹,

Chen²,

Yuan³

et al. 2020

J. Cancer

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Background: Immunotherapy targeting PD-1/PD-L1 represents a breakthrough in the treatment of lung cancer. Pyruvate kinase M2 (PKM2) is not only a critical player in glycolysis, but also conducive to tumor progression and immune response. While both have been linked to lung adenocarcinoma (AC), the correlation and clinical significance of PKM2 and PD-L1 expression in human lung AC tissues remains not entirely explored. Methods: Expression of PKM2 and PD-L1 proteins were detected by immunohistochemistry in 74 lung AC cases and the corresponding noncancerous tissues. Simultaneously, multiplex immunofluorescence was used to detect PKM2, PD-L1, CK, CD3, and CD68 in the lung AC tissues. We measured expression patterns and co-localization of these markers, evaluating their association with clinicopathological features and overall survival. Validation of findings was conducted using mRNA expression data from The Cancer Genome Atlas (TCGA) of 515 lung AC cases. Results: High expression of PKM2 in tumor cells was significantly related with lymph node metastasis and TNM stage (p=0.035, p=0.017, respectively). Moreover, PKM2 expression in tumor cells was positively correlated with tumor PD-L1 expression. High expression of PKM2, PD-L1 in tumor cells and immune cells predicted high mortality rate and poorer survival rates, respectively. Additionally, multivariate Cox regression models indicated that high expression of PKM2 in tumor cells was an independent prognostic factor. Based on TCGA genomic data, high PKM2 mRNA expression was significantly associated with poorer survival (p=0.001). Conclusion: High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict poorer survival rates in patients with lung AC.

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“…This highly glycolytic phenotype is characterized by high expression of glycolysis-associated genes that encode glucose transporters and enzymes involved in aerobic glycolysis. For example, in melanoma, high expression levels of glycolytic proteins such as GAPDH and PKM2 were associated with worse clinical outcome in stage III melanoma (39,40). Additionally, GLUT1 was highly expressed in melanoma tissues and revealed to enhance the metastasis of malignant melanoma cells (41).…”

Section: Discussionmentioning

confidence: 99%

FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

Dong

Yang

et al. 2020

Int J Oncol

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Melanoma, the most aggressive human skin tumor, has a very short survival time, and there are currently no effective treatments. Alterations in cell metabolism, such as enhanced aerobic glycolysis, have been identified as hallmarks of cancer cells. In the present study, bioinformatics studies using online databases revealed that FOXO3a expression was lower in melanoma tissues compared with normal tissues and nevus. Additionally, Kaplan-Meier analysis showed that high expression of FOXO3a predicted an improved prognosis for patients with melanoma. Furthermore, Pearson correlation analysis indicated that the expression of FOXO3a was positively correlated with SIRT6 expression and negatively correlated with the expression levels of a number of glycolysis-associated genes. Chromatin immunoprecipitation and luciferase assays showed that FOXO3a was enriched in the SIRT6 promoter region and promoted its transcription. Then, SIRT6 was overexpressed in FOXO3a-knockdown MV3 cells and downregulated in FOXO3a-overexpressing MV3 cells by using lentivirus-mediated stable infection. The results showed that SIRT6 knockdown or overexpression rescued the effects of FOXO3a overexpression or knockdown, respectively, on glycolysis, as determined by glucose uptake, glucose consumption and lactate production assays, the expression of glycolytic genes and glucose stress flux tests. SIRT6 overexpression also suppressed FOXO3a knockdown-induced tumor growth in a mouse model. The present findings indicated that the FOXO3a-SIRT6 regulatory axis inhibited glucose metabolism and tumor cell proliferation in melanoma, and provided novel insight into potential therapeutic strategies to treat this disease.

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Prognostic implications of markers of the metabolic phenotype in human cutaneous melanoma

Abstract: This summary relates to https://doi.

Cited by 20 publications

References 51 publications

Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract

Cancer Glycolytic Dependence as a New Target of Olive Leaf Extract

High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict worse survival in human lung adenocarcinoma

FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

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