In a recent study published in the Proceedings of the National Academy of Sciences, BCRF researcher Dr. Andrew Ewald and his colleagues report findings that support earlier observations that statins have anti-tumor activity.
More than 35 million Americans take statins to reduce their blood cholesterol levels, making them among the most widely prescribed medications in the world. The work, led by Dr. Ewald and his colleague, Dr. Peter N. Devreotes, shows that cancer cells depend on a nutrient uptake pathway that statins disrupt, causing the cells to starve to death.
The authors did not intend to uncover details about the known negative effect that statins have on cancer cells. Rather, their investigation set out find a drug that would target and kill cancer cells.
Targeting a signaling network to kill cancer cells
Tumor suppressor genes and oncogenes are well-known to cause uncontrolled growth of cancer cells when mutated, but mutations in these genes also have negative effects on cells’ movement, among other functions. Both cellular growth and movement are controlled by a network of proteins that relays signals within the cell. Though the signaling networks are independent, they share proteins and are connected in another way: Growth relies on the cell’s ability to move and respond to its environment and take up nutrients. The researchers speculated that using a drug to target and disrupt an essential protein signaling network that is already perturbed by an oncogenic mutation would be enough to kill cancer cells.
Depleting a molecule crucial for cell movement
The investigators started by screening a library of 2,560 FDA-approved drugs to see which ones could kill cells engineered to have a mutation in the PTEN gene. PTEN codes for a protein that suppresses tumor growth, and, when mutated, the protein cannot function. The researchers found that statins, particularly one type called pitavastatin (Livalo®) most effectively killed PTEN-mutated cells without affecting normal cells.
Next, the team investigated how statins affect cancer cells on a molecular level. To lower blood cholesterol levels, statins block a liver enzyme that makes cholesterol. By testing several intermediate molecules along the pathway that blocks cholesterol production, the researchers determined that pitavastatin kills cells by depleting a molecule called geranylgeranyl pyrophosphate (GGPP). GGPP is responsible for connecting cellular proteins to cellular membranes, including proteins that control cell movement. The team interestingly observed that when given pitavastatin, the PTEN-mutated cells stopped moving before they began to die.
How lack of movement leads to starvation in cancer cells
Cancer cells grow rapidly by consuming substantial amounts of nutrients from their environment. Cells do this through a process called macropinocytosis whereby they essentially form a protrusion to surround and “drink” proteins from their surroundings. Knowing that cancer cells rely heavily on this process for energy, the researchers then tested the idea that GGPP depletion leads to defective macropinocytosis and starvation by adding proteins to the cells’ environment attached to trackable tags. During treatment with pitavastatin, normal cells were full of the tagged proteins but the PTEN-mutated cells were not able to take them up. The team concluded that because cancer cells treated with statins are unable to move and form the protrusions needed to consume nutrients and fuel their growth, they eventually starve.
Cancer cells, including breast cancer, are thought to depend more on constant access to GGPP than normal cells. So, the researchers tested whether statins are toxic to other cancer models beyond the cells they tested. They looked at cells expressing KRasG12V (a common oncogene) and three breast cancer experimental models each expressing a genetic defect in basal, luminal, or epithelial mammary cells. Each of the models was susceptible to pitavastatin, showing that GGPP sensitivity may be a common feature of all cancer cells.
“This paper highlights the importance of understanding how specific treatments kill breast cancer cells, at the molecular level, so that we can use them most effectively,” Ewald said.
What this means for patients
An effective cancer drug targets the cancer cells while leaving normal cells intact. Dr. Ewald and his collaborators have demonstrated that the effects of statins and other GGPP inhibitors to selectively kill cancer cells are worth further research. While still in early stages and far from being a cancer treatment, statins have the potential to become or inform novel cancer therapies. Dr. Ewald and his team are working with oncologists at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins to apply their insights into pitavastatin to move their discovery forward.
“This collaboration was critically enabled by the flexibility that BCRF gives to investigators to pursue our best, most current ideas,” Ewald said. “BCRF funding [allowed] us to rapidly test the exciting concept developed in the Devreotes Lab across a series of relevant preclinical cancer models, greatly accelerating its progress toward the clinic.”
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