Abstract
We have previously reported that expression of NMI (N-myc and STAT interactor) is compromised in invasive breast cancers. We also demonstrated that loss of NMI expression promotes epithelial-mesenchymal-transition and results in enhanced invasive ability of breast cancer cells. Additionally we had demonstrated that restoration of NMI expression reduced breast cancer xenograft growth and downregulated Wnt and TGFβ/SMAD signaling. Here we present our observations that NMI expression drives autophagy. Our studies were promoted by our observation that NMI expressing breast cancer cells showed autophagic vacuoles and LC3 processing. Additionally, we found that NMI expression increased the cisplatin sensitivity of the breast cancer cells. Our mechanistic investigations show that NMI prompts activation of GSK3-β. This multifunctional kinase is an upstream effector of the TSC1/TSC2 complex that regulates mTOR signaling. Inhibition of GSK3-β activity in NMI expressing cells activated mTOR signaling and decreased the cells’ autophagic response. Additionally we demonstrate that a key component of autophagy, DNA-damage regulated autophagy modulator 1 (DRAM1), is regulated by NMI. Our TCGA database analysis reveals concurrent expression of NMI and DRAM1 in breast cancer specimens. We present evidence that NMI sensitizes breast cancer cells to cisplatin treatment through DRAM1 dependent autophagy.
Highlights
Autophagy is a cellular recycling/scavenging process that delivers cytoplasmic components to the lysosomes for degradation
We demonstrate that loss of NMI reduces the autophagy responsiveness of breast cancer cells and renders them more resistant to chemotherapeutic treatment
Its roles are quite dubious in the context of cancer where multiple studies have shown autophagy to serve as a mechanism of cell survival under adverse conditions or a mechanism that prompts cell death[35,36,37]
Summary
Autophagy is a cellular recycling/scavenging process that delivers cytoplasmic components to the lysosomes for degradation. Previous studies from our group have determined that NMI expression is notably reduced during progression of advanced, invasive breast tumors[13,14,15]. We noticed that restoring NMI expression in tumorigenic and metastatic cell lines reduced their tumor xenograft growth rates accompanied by suppression of the Wnt/β -catenin signaling www.nature.com/scientificreports/. The Wnt/β -catenin signaling and autophagy pathways play important roles during development, tissue homeostasis and tumorigenesis. The Wnt/β -catenin signaling pathway has been shown to negatively regulate both basal and stress-induced autophagy[17]. We describe our findings that show a novel role of NMI in prompting autophagic induction of breast cancer cells through a GSK3β signaling cascade. We demonstrate that loss of NMI reduces the autophagy responsiveness of breast cancer cells and renders them more resistant to chemotherapeutic treatment
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