Doxorubicin-Induced Autophagolysosome Formation Is Partly Prevented by Mitochondrial ROS Elimination in DOX-Resistant Breast Cancer Cells

Abstract

Since its discovery, mitophagy has been viewed as a protective mechanism used by cancer cells to prevent the induction of mitochondrial apoptosis. Most cancer treatments directly or indirectly cause mitochondrial dysfunction in order to trigger signals for cell death. Elimination of these dysfunctional mitochondria by mitophagy could thus prevent the initiation of the apoptotic cascade. In breast cancer patients, resistance to doxorubicin (DOX), one of the most widely used cancer drugs, is an important cause of poor clinical outcomes. However, the role played by mitophagy in the context of DOX resistance in breast cancer cells is not well understood. We therefore tried to determine whether an increase in mitophagic flux was associated with the resistance of breast cancer cells to DOX. Our first objective was to explore whether DOX-resistant breast cancer cells were characterized by conditions that favor mitophagy induction. We next tried to determine whether mitophagic flux was increased in DOX-resistant cells in response to DOX treatment. For this purpose, the parental (MCF-7) and DOX-resistant (MCF-7dox) breast cancer cell lines were used. Our results show that mitochondrial reactive oxygen species (ROS) production and hypoxia-inducible factor-1 alpha (HIF-1 alpha) expression are higher in MCF-7dox in a basal condition compared to MCF-7, suggesting DOX-resistant breast cancer cells are prone to stimuli to induce a mitophagy-related event. Our results also showed that, in response to DOX, autophagolysosome formation is induced in DOX-resistant breast cancer cells. This mitophagic step following DOX treatment seems to be partly due to mitochondrial ROS production as autophagolysosome formation is moderately decreased by the mitochondrial antioxidant mitoTEMPO.

Breast Cancer With Increased Drug Resistance, Invasion Ability, and Cancer Stem Cell Property Through Metabolism Reprogramming

“…The results of this study revealed high glucose consumption in the MCF-7 cells with drug resistance. Similarly, Ahmadpour et al demonstrated that lactate production and glucose consumption were higher in MCF-7 cells with doxorubicin resistance than in parental MCF-7 cells, suggesting that MCF-7 drug-resistant cells exhibit a predominance of glycolytic metabolism [37]. Our data revealed that in the MCF-7-D500 cells, G6P and FBP levels were signi cantly increased, whereas those of 2PE and DHAP were signi cantly decreased.…”

“…Reactive oxygen species (ROS) production in mitochondria was higher in MCF-7 cells with doxorubicin resistance than in parental MCF-7 cells [37]. Excessive ROS production may lead to a glycolysis reaction switch to the HBP through the inhibition of the glycolytic enzyme GAPDH [44,45].…”

The Long Non-Coding RNA SAMMSON Is a Regulator of Chemosensitivity and Metabolic Orientation in MCF-7 Doxorubicin-Resistant Breast Cancer Cells

“…Furthermore, targeting glycolysis by targeting glucose transporters or enzymes of the glycolytic pathway can reverse chemoresistance [ 33 ]. Mitochondrial impairment was recently described in MCF-7dox cells with a predominant glycolytic metabolism, with a strong impairment of Cx I structure and function [ 34 ]. Our study further demonstrates that silencing SAMMSON in this model not only enables us to slow glycolysis down, but it also triggers a stimulation of the oxidative metabolism by increasing mitochondrial translation pathways.…”

“…Research has recently provided evidence of a high ROS production in MCF-7dox cells [ 34 ]. In the present study, we showed that the silencing of SAMMSON decreased this ROS production.…”

A Four-Step Cascade Drug-Release Management Strategy for Transcatheter Arterial Chemoembolization (TACE) Therapeutic Applications

“…According to the concept of patient-focused design, vascular embolism is a local treatment that has fewer side effects than chemotherapy. The second and third steps adopted both a nanoparticle strategy and codelivery strategy, combining graphene nanoparticles with the chemotherapy drug doxorubicin (Dox) [6]. Nanoparticles were used as the drug carrier, as they can prolong the retention time of the drug in the blood as well as reduce opsonin absorption and reticuloendothelial system (RES) recognition [7].…”