Abstract
Epithelial mesenchymal transition is a common mechanism leading to metastatic dissemination and cancer progression. In an effort to better understand this process we found an intersection of Nrf2/NLE2F2 (Nrf2), epithelial mesenchymal transition (EMT), and metabolic alterations using multiple in vitro and in vivo approaches. Nrf2 is a key transcription factor controlling the expression of redox regulators to establish cellular redox homeostasis. Nrf2 has been shown to exert both cancer inhibitory and stimulatory activities. Using multiple isogenic non-small cell lung cancer (NSCLC) cell lines, we observed a reduction of Nrf2 protein and activity in a prometastatic mesenchymal cell state and increased reactive oxygen species. Knockdown of Nrf2 promoted a mesenchymal phenotype and reduced glycolytic, TCA cycle and lipogenic output from both glucose and glutamine in the isogenic cell models; while overexpression of Nrf2 promoted a more epithelial phenotype and metabolic reactivation. In both Nrf2 knockout mice and in NSCLC patient samples, Nrf2low was co-correlated with markedly decreased expression of glycolytic, lipogenic, and mesenchymal RNAs. Conversely, Nrf2high was associated with partial mesenchymal epithelial transition and increased expression of metabolic RNAs. The impact of Nrf2 on epithelial and mesenchymal cancer cell states and metabolic output provide an additional context to Nrf2 function in cancer initiation and progression, with implications for therapeutic inhibition of Nrf2 in cancer treatment.
Highlights
The initiation and progression of adenocarcinomas of the lung alter networks important in cell stemness and differentiation state, in both epithelial and associated stroma
We investigated the metabolic reprogramming associated with epithelial mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) adenocarcinoma models reflecting a reversible metastable EMT state (Figure 1A)
Migratory tumor cells can exist in a quiescent mesenchymal state, with the potential for re-epithelialization, re-acquisition of a proliferative phenotype, and metastatic outgrowth [15,22]
Summary
The initiation and progression of adenocarcinomas of the lung alter networks important in cell stemness and differentiation state, in both epithelial and associated stroma. The capacity of cancer cells to undergo epithelial mesenchymal transition (EMT) is strongly implicated as an important driver of tumor cell metastasis and of resistance to therapy [4,5]. This form of cell plasticity is associated with the acquisition of enhanced migratory/invasive cell programs and activation of anti-apoptotic and drug/radiation resistance programs [6,7,8,9,10]. Migratory mesenchymal-like cells can undergo a reverse transition back to a more epithelial state through which cells regain proliferative potential and can establish metastases with phenotypic and mutational characteristics similar to the original primary tumor [15]. The effective therapeutic targeting of these reversible /metastable and sarcomatoid cancer states is an unmet medical need [20,21], in part due to the high degree of cellular heterogeneity [22] and the acquisition of parallel signaling pathways within individual cells
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