Protein interaction could point to new Cushing’s treatment approach
One protein may ease pituitary tumors by blocking another
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The interaction between two proteins may play a role in Cushing’s disease tumors, potentially signaling a new approach to treatment, a study found.
The PPP1R17 protein may help pituitary tumors that cause Cushing’s grow by blocking the activity of another protein, PP2A.
Gilenya (fingolimod), a treatment approved in the U.S. for multiple sclerosis, slowed tumor growth in mice by restoring PP2A activity, but its potential to treat Cushing’s tumors in patients remains unknown.
“This pathway can be pharmacologically targeted in vitro [in lab-grown cells] and in vivo [in lab animals] using fingolimod, an U.S. Food and Drug Administration-approved small molecule, potentially a therapeutic strategy for patients with [Cushing’s disease],” the researchers wrote.
The study, “Phosphoproteomic dysregulation promotes tumor proliferation in Cushing’s disease,” was published in PNAS.
Few effective treatments
Cushing’s disease is caused when adenomas, usually noncancerous tumors in the brain’s pituitary gland, produce excessive amounts of adrenocorticotropic hormone (ACTH), which stimulates cortisol production. ACTH signals the adrenal glands atop the kidneys to produce cortisol. Excess cortisol can cause a wide range of Cushing’s symptoms.
Surgery is the main treatment. However, as an invasive procedure, it can carry risks, and tumors sometimes return.
The team said there are few effective Cushing’s treatments, partly because researchers do not yet fully understand how these tumors develop and grow.
Most pituitary tumors do not contain a known disease-causing mutation. For their study, the researchers focused on another possible mechanism: epigenetic changes. Epigenetics changes how genes are turned on or off without changing the DNA sequence itself. These changes can disrupt the normal balance between kinases (a type of protein), which add phosphate groups to other proteins, and phosphatases, which remove them.
The researchers first found that compared with nearby normal pituitary tissue, pituitary tumors had overactive PPP1R17 genes. PPP1R17 is normally active during early development but becomes mostly inactive in adulthood. In pituitary tumors, its DNA region was more accessible and less methylated — a type of epigenetic change —making the gene easier to activate.
PPP1R17 provides instructions to produce a protein that inhibits two phosphatases, PP1 and PP2A. PP2A is especially important because it acts as a tumor suppressor, meaning it normally helps prevent cells from growing uncontrollably. When PPP1R17 is increased, PP2A activity is reduced, allowing growth-promoting signals to remain active longer than they should.
The researchers confirmed that PPP1R17 physically interacts with PP2A in pituitary tumors. When they increased PPP1R17 in normal mouse pituitary cells cultured in a lab, the cells developed tumor-like changes. The proteins AKT, ERK, and S6 became more phosphorylated, a change that cells understand as a signal to multiply.
PPP1R17 also increased the activity of RNA polymerase II, the cellular machinery that copies DNA into messenger RNA precursors (molecules that carry instructions to produce proteins). This suggests that blocking PP2A causes broader changes in gene activity. The altered cells showed increased activity in other pathways that control growth.
The researchers then tested whether restoring activity in the PP2A signaling pathway could reverse these effects. They studied several PP2A-activating compounds and found that Gilenya reduced the activity of the gene that provides instructions for producing ACTH.
Gilenya also disrupted the interaction between PPP1R17 and PP2A, resulting in slower growth of lab-grown pituitary cells. In mice with implanted pituitary tumors, treatment with Gilenya reduced the size, weight, and volume of the tumors compared with a placebo.
While the number of samples derived from patients was small, and the findings in lab-grown cells and mice still need to be validated, “this work advances our understanding of pituitary adenoma formation and suggests a promising avenue for therapeutic intervention,” the researchers wrote.
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