Abstract
Drug resistance of cancer cells is associated with redox homeostasis. The mechanism of acquired resistance of cancer cells to antitumor drugs is not well understood. Our previous studies revealed that drug resistance and highly expressed P-glycoprotein(P-gp) of MCF-7 breast cancer cells was dependent on intracellular redox homeostasis and declined capacity for scavenging reactive oxygen species (ROS). Recently, we observed that, unlike non-tumorigenic cells MCF-10A, three tumorigenic breast cancer cells (MCF-7S, BT474, MDA-MB-231) reprogrammed their metabolism, highly expressed cystathionine-γ-lyase (CTH), and acquired a particular specialty to utilize methionine (Met) to synthesize glutathione (GSH) through the transsulfuration pathway. Interestingly, doxorubicin (adriamycin, ADR) further reprogrammed metabolism of MCF-7 cells sensitive to ADR (MCF-7S), induced it to be another MCF-7 cell line resistant to ADR (MCF-7R) with dramatically down-regulated CTH. The two MCF-7 cells showed distinctly different phenotypes in terms of intracellular GSH, ROS levels, expression and activity of P-gp, CTH and drug resistance. We showed that CTH modulation or the methionine supply brought about the interconversion between MCF-7S and MCF-7R. Methionine deprivation or CTH silencing induced a resistant MCF-7R and lowered paclitaxel activity, yet methionine supplementation or CTH overexpression reversed the above effects, induced a sensitive phenotype of MCF-7S and significantly increased the cytotoxicity of paclitaxel both in vitro and in vivo. IL-6/STAT3 initiated CTH expression and activity, and the effect on the resistant phenotype was exclusively dependent on CTH and ROS. This study suggests that the IL6/STAT3/CTH axis plays a key role in the transformation between sensitive and resistant MCF-7 cells.
Significance Statement CTH plays a key role in transformation between the sensitive and resistant phenotypes of MCF-7 cells and is dependent on the IL-6/STAT3 signaling axis. Modulation of transsulfuration pathway on CTH or IL-6/STAT3, or methionine supplementation is beneficial to reverse the resistance of MCF-7 cells, which indicates a clinical translation potential.
- breast cancer
- glutathione
- multi-drug resistance
- P glycoprotein (PGP)
- reactive oxygen species (ROS)
- redox regulation
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