Proteomic Analysis Reveals That an Extract of the Plant Lippia origanoides Suppresses Mitochondrial Metabolism in Triple-Negative Breast Cancer Cells

Abstract

Triple-negative breast cancer is an aggressive subtype of breast cancer with low 5-year survival rates, high 3-year recurrence rates, and no known therapeutic targets. Recent studies have indicated that triple-negative breast cancers possess an altered metabolic state with higher rates of glycolysis, mitochondrial oxidative phosphorylation, and increased generation and utilization of tricarboxylic acid cycle intermediates. Here, we utilized label-free quantitative proteomics to gain insight into the anticancer mechanisms of a methanolic extract from the Central American plant Lippia origanoides on MDA-MB-231 triple-negative breast cancer cells. The L. origanoides extract dysregulated mitochondrial oxidative phosphorylation by suppressing the expression of several subunits of Complex I of the electron transport chain, and inhibited cellular metabolism by down-regulating key tricarboxylic acid cycle enzymes and mitochondrial lipid and amino-acid metabolic pathways. Our study also revealed that treatment with the extract activated the stress response and pathways related to cell-cycle progression and DNA repair. Overall, our results reveal compelling new evidence that the extract from L. origanodes triggers rapid irreversible apoptosis in MDA-MB-231 cells by effectively 'starving' the cells of metabolites and ATP. We continue to study the specific bioactive components of the extract in the search for novel, highly effective mitochondrial inhibitors to selectively target triple-negative breast cancer.

Quantitative proteomic analysis of enhanced cellular effects of electrochemotherapy with Cisplatin in triple-negative breast cancer cells

“…MaxQuant (v1.6.1.0) 71,72 was used to process MS/MS data against the Uniprot Homo sapiens fasta (http://www.uniprot.org; 26,446 entries as of October 05, 2018) concatenated with a common contaminants and a reverse-decoy database, as previously 73 . Cleavage enzymes were setup as Trypsin/P and LysC, with toleration of up to 2 missed cleavages.…”

The Natural Products and Extracts: Anti‐Triple‐Negative Breast Cancer in Vitro

“…The above two complexes generated the proton gradient required for the production of ATP by ATP synthetase, and its marked downregulation by L42 resulted in rapid energy consumption in cells and ensuing apoptotic death. [75] The ethanolic (GG-A003) and hydro-alcoholic (GG-A002) extracts of G. glabra exerted suppressive effects on CYP1B1 and CYP1A1 in liver cells with EC 50 values in the range of 16-20 mg/mL. Quercetin (52) and glabrol (53) (Figure 11) were isolated from the roots of G. glabra.…”

Medicinal plants and animals of an important seasonal dry forest in Brazil

“…The ethanolic extract of L. origanoides leaves demonstrate an acaricidal effect against Tetranychus cinnabarinus and the potential for the biological control of pests (Sivira et al 2011). In addition, an extract of L. origanoides leaves was able to inhibit the progression of aggressive breast cancer cells (Raman et al 2017), which was partially associated with its ability to trigger the rapid irreversible apoptosis of cancer cells by reducing mitochondrial oxidative metabolism and ATP levels (Raman et al 2018). The biological effect of this species is associated with its EO.…”