17β‑estradiol‑induced mitochondrial dysfunction and Warburg effect in cervical cancer cells allow cell survival under metabolic stress

Abstract

Mitochondria from different types of cancer show bioenergetics and dysfunction that favor cell proliferation. The mechanistic understanding of estrogen in cervical cancer is poorly understood. Therefore, the objective of this study was to determine how 17β-estradiol (E2) affects mitochondrial function and the Warburg effect in SiHa, HeLa and C33A cervical cancer cells. Mitochondrial compromise was evaluated measuring changes in the membrane permeability by immunofluorescence, calcium concentration, redox status, iron and ferritin reserves. Glucose consumption and lactic acid assays were used to detect the metabolic activity. Results were confirmed at molecular level by analysis of the differential gene expression using RNA sequencing. E2 modified the mitochondrial permeability and produced an alteration in the calcium signaling pathway. In HeLa and SiHa, there was a significant decrease in nitric oxide levels and lipid peroxidation, and an increase in glucose consumption and lactic acid levels when stimulated with E2. Intracellular iron or ferritin reserves were not affected by the E2 treatment. Genes differentially modulated by E2 were involved in the mitochondrial electron transport chain, oxidative phosphorylation system, glycolysis, pentose phosphate pathway and the regulation of metabolic signaling pathways. Herein, we provide evidence for a primary effect of estrogen on mitochondrial function and the Warburg effect, favoring the metabolic adaptation of the cervical cancer cell lines and their survival.

Immune-and Metabolism-Associated Molecular Classification of Ovarian Cancer

“…However, as stated in previous studies, the significance of TNFRSF9 in cancer is not clear, but it was suggested to be immunosuppressive ( 43 – 46 ). Increased expression of TNFRSF9 was observed in platinum resistant ovarian tumors ( 27 , 47 , 48 ), which implies that this gene may promote tumor progression. In this study, we found that the expression level of TNFRSF9 was the highest in the C1 subtype, which make us suspected the high expression of TNFRSF9 may have something to do with the low survival of C1 subtype.…”

A Glycolysis-Related Gene Signature Correlates With the Characteristics of the Tumor Immune Microenvironment and Predicts Prognosis in Patients With Hepatocellular Carcinoma

“…Specifically, the Warburg effect, characterized by high glucose uptake and increased lactate production, is a phenotype commonly exhibited by HCC cells ( Anderson et al, 2018 ; Pascale et al, 2020 ). The Warburg effect results from mitochondrial dysfunction ( Riera Leal et al, 2020 ), tumor adaptation ( Ždralević et al, 2018 ), microenvironmental changes ( Sun et al, 2018 ), oncogenes ( Banks, 2013 ) and abnormalities in related signaling pathways. In the present study, GSEA showed HCC tissues from patients at high risk for poor prognosis were enriched in glycolysis-related genes.…”

Identification of Prognostic Glycolysis-Related lncRNA Signature in Tumor Immune Microenvironment of Hepatocellular Carcinoma

“…Furthermore, 90% of energy in normal tissues comes from tricarboxylic acid cycle in mitochondria (Anderson et al, 2018), while more than 50% of the energy depends on glycolysis, which is known as the "Warburg effect" (Pascale et al, 2020). At present, it is believed that the main mechanisms of Warburg effect include mitochondrial dysfunction (Riera Leal et al, 2020Leal et al, ), tumor adaptation (Ždralević et al, 2018, microenvironment changes (Sun et al, 2018), oncogene (Banks, 2013), and related signal pathway disorders. According to the results of GSEA enrichment analysis, we found that Notch, p53, Wnt, and other signaling pathways are active in the high-risk group whether we use the Hallmark dataset or KEGG dataset.…”