Skip to content

Biomedical Odyssey

Life at the Johns Hopkins School of Medicine

Biomedical Odyssey Home Perspectives in Research Uncovering How a Diabetes Drug Slows Cancer Growth

Uncovering How a Diabetes Drug Slows Cancer Growth

petry dish in the lab

What do a relatively unknown gene, a well-known signaling pathway and nuclear transport have in common? They’re all part of how diabetes and cancer drug metformin works. Metformin is a widely used type 2 diabetes drug that lowers glucose levels and sensitizes cells to insulin.

Metformin’s mechanism has been long sought after, and studies into how it works have revealed that besides its ability to lower blood sugar, it also slows cancer growth. Previous work has shown that metformin compromises mitochondrial energetics and ultimately inactivates the mTORC1 pathway, a well-studied signaling pathway that plays a key role in regulating cell growth and proliferation. But precisely how this happens has remained a mystery.

Now, in a study published in the Dec. 15 issue of Cell, the lab of Alexander Soukas at Massachusetts General Hospital in Boston has uncovered a more complete picture of how metformin’s anticancer properties work. The authors discovered that expression of another gene called ACAD10 is important for metformin’s ability to reduce cancer growth. Also involved is the machinery regulating transport of proteins through pores in the nucleus and mTORC1 activation.

How did the Soukas group connect these seemingly disparate players? It relied upon popular model system Caenorhabditis elegans, a roundworm also known as C. elegans, to find out. When metformin was administered to these animals, the researchers found that a gene called ACAD10 had elevated expression levels. ACAD10, or acyl CoA dehydrogenase family member 10, is not well-studied, but genes similar to it are involved in the breakdown of fatty acids in the mitochondria.

Previous work has shown that well-known signaling pathway mTORC1 was involved in metformin’s action, and the Soukas group confirmed that it was related to the increased levels of ACAD10 observed. Next, the group needed to connect these parts together. The group systematically mutated all of C. elegan’s genes and administered metformin. It then screened for mutants that blocked the drug’s effects, which suggests that the normal, nonmutated gene is a possible target. From this work, the researchers found that several genes belonging to the nuclear pore complex were involved in metformin’s mechanism of action. This complex allows proteins and other molecules to access the nucleus by fitting through pores in its membrane.

Now all the pieces of the puzzle can be fit together. The researchers determined that a critical component involved in activating the mTORC1 signaling pathway, RagC, needed to access the nucleus through the nuclear pore complex. Metformin blocks this movement and thus prevents mTORC1 from being activated. This then induces the expression of ACAD10, which ultimately slows cancer growth.

These findings shed light on how metformin, a widely prescribed diabetes drug, can also act to slow cancer growth. Although its anticancer properties were discovered early on, this work provides more mechanistic details of the pathway and gives researchers new pharmacological targets for specifically attacking cancer cells. Similarly, these new insights into mTORC1 signaling offer an interesting example of how inactivating one pathway (mTORC1) can activate a seemingly unrelated gene (ACAD10) with big implications for the overall health of an organism. Much more work is needed to fully understand this phenomenon, but connecting these components is a good start.

Related Content