Pituitary Protein PROP1 a Potential Therapeutic Target for Cushing’s

The protein may play a role in disease-causing tumors, small study suggests

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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PROP1, a pituitary gland protein that regulates gene activity related to hormone production, may play a role in the development of noncancerous tumors that cause Cushing’s disease, a small preliminary study suggested.

According to researchers, PROP1 may be a therapeutic target for pituitary tumors. Future studies involving a larger number of patients are needed to understand PROP1’s mechanism of action in tumor development.

The study, “Contribution of PROP1 in the pathogenesis of Cushing’s disease: A preliminary study,” was published in the journal Interdisciplinary Neurosurgery.

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The brain’s pituitary gland produces and secretes (releases) hormones to regulate various bodily processes. Noncancerous tumors called adenomas can grow in the pituitary gland and disrupt hormone secretion, leading to multiple diseases.

In Cushing’s, such tumors, referred to as corticotroph adenomas, trigger the excess production of adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal glands sitting atop the kidneys to produce excessive amounts of cortisol.

In comparison, acromegaly is a condition marked by the presence of somatotroph adenomas in the pituitary gland. These tumors release excessive amounts of growth hormone, causing the body to become oversized.

In the pituitary gland, PROP1 is a protein that controls the activity of the PIT1 gene, which stimulates precursor cells to mature into different cell types that secrete various hormones. PROP1 has also been reported to be present in all kinds of pituitary adenomas and, as such, may play a role in the development of corticotroph adenomas in Cushing’s.

The study and its results

To find out, researchers in Japan measured PROP1 protein expression (levels) in pituitary adenomas using immunohistochemistry — a method that detects PROP1 by staining tissue samples with a highly selective antibody. This technique accounted for PROP1 levels measured in normal tissue found near the tumor, so only adenoma-specific PROP1 was considered.

“This study is the first report to analyze PROP1 expression in pituitary adenomas by immunohistochemistry,” the team wrote.

The team examined pituitary adenoma tissues collected from six Cushing’s disease patients, ages 33–75, who underwent tumor removal surgery — a procedure called transsphenoidal adenomectomy, which is considered a first-line treatment for Cushing’s disease.

Initial experiments confirmed the expression of ACTH and TPIT, a marker of corticotroph adenomas, in pituitary adenoma tissues, but not growth hormone or PIT1, which is typically indicative of somatotroph adenomas.

PROP1 was expressed in three out of six Cushing’s patients and was frequently found in adenoma tissues that also contained TIPT.

In somatotroph adenomas that cause acromegaly, tumor cells that stain positive for a protein called CAM5.2 and show a diffuse-type pattern are more mature, or differentiated. These mature cells resemble normal growth hormone-producing cells. As such, CAM5.2 may reflect the degree of maturation of cells in ACTH-producing tumors.

ACTH levels were elevated in corticotroph adenomas with a diffuse CAM5.2 staining pattern, or more mature cells, although this increase was not considered statistically significant.

“It is likely that diffuse-type adenomas are composed of more differentiated tumor cells,” they wrote.

In the three cases where tissue tested positive for PROP1, CAM5.2 staining showed a nondiffuse pattern, indicating cells that are still differentiating and are less mature. In contrast, PROP1 was not expressed in tissues from the other three cases where CAM5.2 staining pattern was diffuse, signaling the presence of mature cells.

Consistently, PROP1 was more frequently positive in Cushing’s disease tissue with a nondiffuse CAM5.2 staining pattern, although this was not statistically significant.

“This result suggests that PROP1 is more prominently expressed in less differentiated corticotroph adenomas,” the researchers wrote.

“PROP1 was prominently expressed in less differentiated corticotroph adenomas of the TPIT, but not PIT1, lineage, suggesting that PROP1 is more than just an upstream regulator of PIT1 in pituitary adenomas,” they wrote.

“PROP1 may have a role in [the development] of pituitary adenomas in Cushing’s disease,” they wrote, adding that it is “expected to be a new therapeutic target for refractory pituitary adenomas.”