Metformin action on Nuclear transport
Abstract
The nuclear pore complex (NPC), the sole gateway between the nucleus and the cytoplasm for macromolecules, facilitates protein transport between the two compartments. In young, healthy cells, there is a size threshold below which proteins can diffuse across the NPC via passive transport with little impedance. In aging and disease, the latter is known to deteriorate, leading to much more promiscuous transport of larger molecules that are typically restricted from passage through the NPC in a healthier, younger cell. However, this deterioration of the NPC can be halted or even reversed by metformin, a member of the biguanide class of drugs commonly prescribed in type 2 diabetes. We previously demonstrated that metformin action in aging and cancer requires intact function of the NPC, that is, that mutations in or reduced function of key nucleoporins (proteins that make up the NPC), lead to resistance to the prolongevity and anticancer effects of biguanides, including metformin and the related compound phenformin. To fully understand the molecular mechanism for this finding, we studied the dynamics of nucleocytoplasmic transport in transformed cells with biguanide treatment. We leveraged fluorescently-labeled dextran molecules in HeLa cells as a model system and examined passive nuclear import through the NPC in digitonin-permeabilized cells. Phenformin leads to a dose- and time-dependent restriction of passive nucleocytoplasmic transport. We find that biguanide action on…
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