Metabolic regulation of Sirtuins upon fasting and the implication for cancer.
Fasting could also slow the tumor growth and augment the efficacy of certain systemic agents/chemotherapy drugs in various cancer. The mechanism behind this proposed idea may be due to, at least in some part, the metabolic regulation by Sirtuin family proteins whose functions are involved in specific aspects of longevity, stress response and metabolism. Sirtuin, particularly SIRT1 and SIRT3, can be activated by fasting and further exhibit their effects in insulin response, antioxidant defense, and glycolysis. Therefore, sirtuin may have anticancer effects by shifting metabolism to a less proliferative cell phenotype as well as less prone to oxidative stress attack.
SIRT1, SIRT6 and SIRT7are nuclear sirtuin, which regulate several critical transcription factors of many metabolic pathways [53,54]. SIRT2 is located primarily in cytoplasm and is able to regulate cellular mitosis to prevent genomic instability [10,13]. SIRT3, SIRT4 and SIRT5are located in mitochondria.
SIRT3 has been demonstrated to be a legitimate tumor suppressor by regulating mitochondrial energy homeostasis, suppressing ROS production via MnSOD deacetylation [14,19,55], whereas SIRT4 functions as a tumor suppressor as well by mediating a DNA damage dependent block in glutamine metabolism . SirtuinrequireNADþ as a cofactor to deacetylate target proteins and modify their function and as such, it has been proposed that sirtuinare at the nexus of cellular energy metabolic regulation which provides a possible link between cellular energy status and metabolicpathways