Metformin as an Anticancer Agent.

Metformin has been a frontline therapy for type 2 diabetes (T2D) for many years. Its effectiveness in T2D treatment is mostly attributed to its suppression of hepatic gluconeogenesis; however, the mechanistic aspects of metformin action remain elusive. In addition to its glucose-lowering effect, metformin possesses other pleiotropic health-promoting effects that include reduced cancer risk and tumorigenesis. Metformin inhibits the electron transport chain (ETC) and ATP synthesis; however, recent data reveal that metformin regulates AMP-activated protein kinase (AMPK) and the mechanistic target of rapamycin complex 1 (mTORC1) by multiple, mutually nonexclusive mechanisms that do not necessarily depend on the inhibition of ETC and the cellular ATP level. In this review, we discuss recent advances in elucidating the molecular mechanisms that are relevant for metformin use in cancer treatment. Highlights Metformin use is associated with lower cancer incidence in diabetic patients and is considered for cancer therapy of non-diabetic patients. Metformin inhibits ETC and elevates AMP/ATP ratio, resulting in AMPK activation and mTORC1 inhibition. In addition, at metformin concentrations that do not affect the ETC and AMP/ATP ratio, administration of metformin results in AMPK activation and mTORC1 inhibition by mechanisms not involving ETC. Metformin-induced inhibition of ATP synthesis affects the nuclear pore complex, which leads to nuclear exclusion of RagC. Without being able to pass through the nucleus, RagC cannot be potentiated for mTORC1 activation. [ABSTRACT FROM AUTHOR]