Statins Can Destroy Cancer-Causing Mutated Proteins

Statins could be used for more than just lowering cholesterol.

In a study published in Nature Cell Biology, investigators found that the use of statins could shut down structurally mutated p53 proteins—–which can accelerate cancer progression––while causing no harm to proteins produced by healthy p53 genes.

“I could have kept working for 20 years or longer without any big finding,” said study author Tomoo Iwakuma, MD, PhD. “This is the most exciting work of my science life, because it will contribute to treating cancer.”

When p53 works correctly, it produces proteins that prevent cells from rapidly growing and dividing. But when the gene becomes mutated, its regulatory abilities are compromised, allowing cells to grow out of control, develop tumors, and spread. The mutated p53 accelerates the progression of cancer and drug resistance.

For the study, investigators sought to eliminate the mutant proteins, while leaving cells containing healthy p53.

Four years ago, the investigators collaborated with the High Throughput Screening Laboratory (HTC) at the University of Kansas. They screened nearly 9000 compounds to determine which ones could degrade mutant p53. Approximately 2400 of the screened compounds were FDA-approved, while the others were uncharacterized compounds that were not FDA-approved.

After receiving a list of 10 promising compounds, Iwakuma was shocked to find that some of them were statins. Since early screenings can often produce false-positives, the investigators had to verify the lab results by first testing them in cells and then in mice.

The mice were injected with cells containing mutant p53. Once the tumors formed, the investigators treated them with high doses of statins for 21 days.

The results of the study showed that tumors were unable to grow as well in mice treated with statins compared with the controls. The statins worked only on structurally mutated p53, rather than p53 mutated at the area that binds to DNA.

“We found that only the structural mutation is affects,” Iwakuma said. “Which explains why clinical studies with statins were inconclusive.”

Despite the study results, the authors noted that more research was needed.

“Once we knew for sure statins degraded mutant p53, we still had to figure out how,” said co-author Atul Ranjan, PhD. “We needed to find out exactly how the statins work for p53 degradation; which other proteins are involved in the mechanism.”

Co-author Alejandro Parrales, PhD, examined heat shock proteins as a potential candidate because of their ability to correct misfolded proteins.

The investigators identified DNAJA1 as a heat shock protein that binds to misfolded mutant p53, thereby protecting the mutant p52 from an enzyme that flags damaged proteins for destruction.

The results showed that the same mechanism that helps statins reduce cholesterol also prevented mutant p53 from binding to DNAJA1, causing the mutant proteins to go unprotected. This resulted in mutant p53 attaching to the enzyme that leads to its degradation.

Fortunately, mutant p53 are not usually present in normal cells, meaning the process does not affect healthy cells.

The authors noted that more research needs to be done, such as finding ways to directly target DNAJA1. Additionally, statins or other p53 degrading drugs have the potential to be used in conjunction with chemotherapy.