AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress

A mechanism is suggested that helps tumour cells survive energy stress conditions during early stages of tumorigenesis. LKB1 is a tumour suppressor, but in certain contexts, it has also been implicated in promoting cell transformation. Nissim Hay and colleagues now show that under metabolic stress, the LKB1–AMPK pathway is important for maintaining NADPH homeostasis, through regulation of the balance between fatty acid synthesis and oxidation, mediated by the acetyl-CoA carboxylases ACC1 and ACC2. This pathway is shown to promote cancer-cell survival and tumour growth. The authors suggest that this mechanism operates during the early stages of tumorigenesis, to help tumour cells to survive energy stress conditions. Overcoming metabolic stress is a critical step for solid tumour growth1,2. However, the underlying mechanisms of cell death and survival under metabolic stress are not well understood. A key signalling pathway involved in metabolic adaptation is the liver kinase B1 (LKB1)–AMP-activated protein kinase (AMPK) pathway2,3. Energy stress conditions that decrease intracellular ATP levels below a certain level promote AMPK activation by LKB1. Previous studies showed that LKB1-deficient or AMPK-deficient cells are resistant to oncogenic transformation and tumorigenesis4,5,6, possibly because of the function of AMPK in metabolic adaptation. However, the mechanisms by which AMPK promotes metabolic adaptation in tumour cells are not fully understood. Here we show that AMPK activation, during energy stress, prolongs cell survival by redox regulation. Under these conditions, NADPH generation by the pentose phosphate pathway is impaired, but AMPK induces alternative routes to maintain NADPH and inhibit cell death. The inhibition of the acetyl-CoA carboxylases ACC1 and ACC2 by AMPK maintains NADPH levels by decreasing NADPH consumption in fatty-acid synthesis and increasing NADPH generation by means of fatty-acid oxidation. Knockdown of either ACC1 or ACC2 compensates for AMPK activation and facilitates anchorage-independent growth and solid tumour formation in vivo, whereas the activation of ACC1 or ACC2 attenuates these processes. Thus AMPK, in addition to its function in ATP homeostasis, has a key function in NADPH maintenance, which is critical for cancer cell survival under energy stress conditions, such as glucose limitations, anchorage-independent growth and solid tumour formation in vivo.