Cancer: The Metabolic Link
After decades of research into the genetics of cancer, there has been amassing evidence associating these cancer causing genes, or oncogenes, to cellular metabolism and bioenergetics regulation. This metabolic link serves to facilitate the rapid growth and survival that is characteristic of many cancer cells. Given this, it is not surprising that obesity, already known to exacerbate metabolic disorders, is also affiliated with increased cancer risk. As obesity approaches pandemic levels, understanding the mechanisms involved between cancer and organism metabolism becomes increasingly important.
AMP in Energy Homeostasis:
AMP-activated protein kinase (AMPK) is an important mediator in maintaining cellular energy homeostasis. In response to a shortage of energy, AMPK can be activated to promote ATP production and regulate metabolic energy, such as stimulating fatty acid oxidation, enhancing insulin sensitivity, alleviating hyperglycemia and hyperlipidemia, and inhibiting proinflammatory changes. Thus, AMPK is a well-received therapeutic target for both metabolic syndrome and Type 2 diabetes.
AMPK in Cancer:
In 2003, the discovery of the tumor suppressor liver kinase B1 (LKB1) as the major upstream kinase of AMPK established a link between an energy regulator and cancer pathogenesis. This suggests that the tumor suppressor functions of LKB1 could be mediated by AMPK. Consistent with this idea, recent epidemiological studies indicate that treatment with metformin, an AMPK activator reduces the incidence of cancer, prompting enthusiasm for these agents as anti-cancer therapies.
The mechanism by which AMPK is involved with cancer is not yet fully understood. One hypothesis includes AMPK’s role as a metabolic cell cycle checkpoint control. Activation of AMPK by energy shortage (e.g., hypoxia and low levels of nutrients) reprograms cellular metabolism and enforces a metabolic checkpoint on the cell cycle. Thus, loss of such a checkpoint control could lead to unrestrained cell growth. AMPK may function as a metabolic tumor suppressor by regulating glucose, lipid and protein metabolism by acting on mTOR, p53, COX-2, ACC and FASN. This is substantiated by the fact that loss of AMPK signaling is associated with a worse clinical outcome in several cancers such as lung, colon and liver cancer.
Moreover, recent studies have connected metabolic status in the lymphocytes to the cancer development, prevention and treatment. Activation of AMPK could promote survival and anti-tumor function of T cells, in particular CD8+ T cells, resulting in superior tumor suppression in vivo.
Thus, uncovering the molecular mechanisms that govern metabolic reprogramming in the immune system and potential impact on T cell fate, plasticity, and effector function can provide a fundamentally different approach to treating cancer.
