The down-regulation of SLC7A11 enhances ROS induced P-gp over-expression and drug resistance in MCF-7 breast cancer cells

Abstract

Adriamycin (ADR) induces the over-expression of P-glycoprotein (P-gp) and multiple drug resistance in breast cancer cells. However, the biochemical process and underlying mechanisms are not clear. Our previous study revealed that ADR increased reactive oxygen species (ROS) generation and decreased glutathione (GSH) biosynthesis, while N-acetylcysteine, the ROS scavenger, reversed the over-expression of P-gp. The present study showed that ADR inhibited the influx of cystine (the source material of GSH) and the activity of the SLC7A11 transporter (in charge of cystine uptake) in MCF-7 cells. For the first time, we showed that the down-regulation/silence of SLC7A11, or cystine deprivation, or enhanced ROS exposure significantly increased P-gp expression in MCF-7 cells. The down-regulation of SLC7A11 markedly enhanced ROS induced P-gp over-expression and drug resistance in MCF-7 cells; a combination of either an inhibited/silenced SLC7A11 or cystine deprivation and increased ROS dramatically promoted P-gp expression, which could be reversed by N-acetylcysteine. In contrast, the over-expression of SLC7A11, or supplementation with sufficiently cystine, or treatment with N-acetylcysteine significantly decreased P-gp expression and activity. It was suggested that ROS and SLC7A11/cystine were the two relevant factors responsible for the expression and function of P-gp, and that SLC7A11 might be a potential target modulating ADR resistance.

Targeting ferroptosis in breast cancer

“…RNA sequencing analysis has revealed that SLC7A11 is upregulated in brain metastatic breast cancer tissues, implying a role for SLC7A11 in breast cancer metastasis [314]. In 2017, Ge et al reported that downregulation of SLC7A11 could confer adriamycin resistance to MCF-7 breast cancer cells by over-expressing P-gp-mediated increased ROS level [315]. In 2018, Bolli et al showed that inhibition of xCT by virus-like-particle immunotherapy could reduce the metastatic potential of breast cancer stem cells [316].…”

Amino Acid Transporters and Glutamine Metabolism in Breast Cancer

“…SLC7A11 is associated with treatment resistance in breast cancer. Adriamycin suppresses SLC7A11 activity and causes overexpression of reactive oxygen species (ROS)-induced P-glycoprotein, resulting in drug resistance [ 63 ]. SLC7A11 is also responsible for distant metastasis of breast cancer.…”

MicroRNA‑145 promotes the apoptosis of leukemic�stem�cells and enhances drug‑resistant K562/ADM cell�sensitivity to adriamycin via the regulation of ABCE1

“…A previous study revealed that high levels of MDR1 and P-gp were associated with chemotherapy sensitivity, high-grade tumors, lymph node metastasis, a poor response and a shorter survival ( 25 ). Ge et al stated that ADM induced the overexpression of P-gp in breast cancer cells, which, in turn, increased the intracellular efflux of ADM ( 26 ). The present study further highlighted that K562/ADM cells were more resistant to ADM, which may provide new insight into leukemic therapies.…”