Abstract
The DNA damage response is essential for sustaining genomic stability and preventing tumorigenesis. However, the fundamental question about the cellular metabolic response to DNA damage remains largely unknown, impeding the development of metabolic interventions that might prevent or treat cancer. Recently, it has been reported that there is a link between cell metabolism and DNA damage response, by repression of glutamine (Gln) entry into mitochondria to support cell cycle arrest and DNA repair. Here, we show that mitochondrial Gln metabolism is a crucial regulator of DNA damage-induced cell death. Mechanistically, inhibition of glutaminase (GLS), the first enzyme for Gln anaplerosis, sensitizes cancer cells to DNA damage by inducing amphiregulin (AREG) that promotes apoptotic cell death. GLS inhibition increases reactive oxygen species production, leading to transcriptional activation of AREG through Max-like protein X (MLX) transcription factor. Moreover, suppression of mitochondrial Gln metabolism results in markedly increased cell death after chemotherapy in vitro and in vivo. The essentiality of this molecular pathway in DNA damage-induced cell death may provide novel metabolic interventions for cancer therapy.
Highlights
Cells encounter many internal and external DNA damages
AREG protein levels were significantly induced in Mitochondrial glutamine (Gln) metabolism regulates cellular the nuclear fractions of BPTES treated cells, and this increase was sensitivity to DNA damage rescued by DMKG (Fig. 2d and Supplementary Fig. 2e)
Since the repression of mitochondrial glutaminolysis has recently investigate the importance of AREG regulation by Gln anaplerosis been linked to proper cellular DNA damage responses such as cell in response to DNA damage, cells were treated with BPTES and/or cycle arrest and DNA repair [10], we hypothesized that mitochon- DMKG followed by DNA damaging agent
Summary
Cells encounter many internal and external DNA damages. To respond to these threats, cells have evolved a tightly orchestrated signaling response from the activation of growth arrest or DNA repair pathways to the initiation of cell death, and defects in these well-coordinated DNA damage responses are frequent causes of genomic instability and human pathologies, such as cancer and aging [1,2,3]. Genotoxic stress suppresses the entry of Gln into the TCA cycle, which is required for proper DNA damage response, and a failure of this metabolic block induces impaired cell cycle arrest and delayed DNA repair [10]. These observations imply that mitochondrial Gln metabolism may have an important, previously undetermined role in cell survival upon DNA damage. It has not well investigated how mitochondrial Gln metabolism regulates DNA damage-induced cell death
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