Fatty acid oxidation and autophagy promote endoxifen resistance and counter the effect of AKT inhibition in ER-positive breast cancer cells

Tamoxifen(TAM)is the first-line endocrine therapy for estrogen receptor-positive(ER+)breast cancer(BC).However,acquired resistance occurs in∼50%cases.Meanwhile,although the PI3K/AKT/mTOR pathway is a viable target for treatment of endocrine therapy-refractory patients,complex signaling feedback loops exist,which can counter the effectiveness of inhibitors of this pathway.Here,we analyzed signaling pathways and metabolism in ER+MCF7 BC cell line and their TAM-resistant derivatives that are co-resistant to endoxifen using immunoblotting,quantitative polymerase chain reaction,and the Agilent Seahorse XF Analyzer.We found that activation of AKT and the energy-sensing kinase AMPK was increased in TAM and endoxifen-resistant cells.Furthermore,ERRα/PGC-1βand their target genes MCAD and CPT-1 were increased and regulated by AMPK,which coincided with increased fatty acid oxidation(FAO)and autophagy in TAM-resistant cells.Inhibition of AKT feedback-activates AMPK and ERRα/PGC-1β-MCAD/CPT-1 with a consequent increase in FAO and autophagy that counters the therapeutic effect of endoxifen and AKT inhibitors.Therefore,our results indicate increased activation of AKT and AMPK with metabolic reprogramming and increased autophagy in TAM-resistant cells.Simultaneous inhibition of AKT and FAO/autophagy is necessary to fully sensitize resistant cells to endoxifen.

Erratum: P53-regulated autophagy and its impact on drug resistance and cell fate

The original article was published on 19 Mar 2021,and the original article link is https://cdrjournal.com/article/view/3789 The corresponding author declared that The Department of Defense Grant support acknowledgment was incorrectly entered.The Department of Defense Grant award that helped support this work was W81XWH-16-1-0025.Therefore,he needed to change financial support and sponsorship in his publication in our journal.According to the evidence provided by the corresponding author,this work was supported by the National Cancer Institute Grant(R01CA200232-05)and the Department of Defense Grant(W81XWH-16-1-0025)both to Maki CG,and all of the other authors of this paper agreed with the change mentioned above.Therefore,we publish this erratum to announce this change.

P53-regulated autophagy and its impact on drug resistance and cell fate

Wild-type p53 is a stress-responsive transcription factor and a potent tumor suppressor.P53 inhibits the growth of incipient cancer cells by blocking their proliferation or inducing their death through apoptosis.Autophagy is a self-eating process that plays a key role in response to stress.During autophagy,organelles and other intracellular components are degraded in autophagolysosomes and the autophagic breakdown products are recycled into metabolic and energy producing pathways needed for survival.P53 can promote or inhibit autophagy depending on its subcellular localization,mutation status,and the level of stress.Blocking autophagy has been reported in several studies to increase p53-mediated apoptosis,revealing that autophagy can influence cell-fate in response to activated p53 and is a potential target to increase p53-dependent tumor suppression.