Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin

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.