How do tumours adapt to nutrient stress?

Reduced blood flow contributes to tumour hypoxia and nutrient deprivation forcing cancer cells to adapt to ensure survival. In this issue of The EMBO Journal, Ye et al show that a stress response pathway including the eIF2 kinase GCN2 and its downstream target, the transcriptional activator ATF4, is critical for proliferation and survival of tumour cells after starvation for amino acids or glucose and is essential for growth in vivo in a xenograft model. This study provides new mechanistic insight into how tumour cells sense and adapt to nutrient restriction and suggests new approaches for cancer chemotherapy. Rapidly growing tumour cells outgrow their blood supply resulting in a microenvironment with reduced oxygen and nutrients. Tumour cells can adapt to this stressful environment by inducing angiogenesis and altering metabolic strategies, thus ensuring survival and proliferation. A study by Ye et al (2010) published in this issue of The EMBO Journal describes a mechanism for how tumour cells sense and adapt to a limited nutrient environment. The key findings are that a stress response pathway featuring the protein kinase GCN2 and its downstream target, the transcription activator ATF4, is critical for survival and proliferation of cultured tumour cells after starvation for amino acids or glucose and for tumour growth in vivo. In response to nutrient deprivation, GCN2 phosphorylates the a subunit of the translation initiation factor, eIF2, thus allowing cells to conserve resources as they reconfigure gene expression to overcome the nutrient stress (Figure 1) (Hinnebusch, 2005; Wek et al, 2006). Concurrent with lowered protein synthesis, eIF2a phosphorylation enhances the translation of select mRNAs, such as that encoding ATF4, a transcription activator of genes involved in metabolism, nutrient uptake, and alleviation of oxidative stress (Harding et al, 2003; Wek et al, 2006). The activation signal for the GCN2/eIF2aBP/ATF4 pathway is uncharged tRNAs that accumulate during nutrient stress and