DEPTOR inhibits cell proliferation and confers sensitivity to dopamine agonist in pituitary adenoma

Area of Science:

• Oncology
• Molecular Biology
• Endocrinology

Background:

• Mechanistic target of rapamycin (mTOR) hyperactivation is implicated in various human tumors.
• The role of DEPTOR, an mTOR-interacting protein, in pituitary adenoma (PA) pathogenesis is largely unexplored.

Purpose of the Study:

• To investigate the role of DEPTOR in pituitary adenoma.
• To explore DEPTOR's potential as a therapeutic target for PAs, particularly dopamine-resistant prolactinomas.

Main Methods:

• Analysis of DEPTOR expression in PA tissues.
• In vitro and in vivo studies using pituitary tumor cell lines (GH3 and MMQ) with DEPTOR manipulation (overexpression and knockdown).
• Assessment of cell proliferation, sensitivity to cabergoline (CAB), mTORC1/mTORC2 activity, E3 ubiquitin ligase βTrCP1 levels, and autophagy-dependent cell death.

Main Results:

• DEPTOR was downregulated in PA tissues, notably in dopamine-resistant prolactinomas.
• DEPTOR overexpression inhibited pituitary tumor cell proliferation and sensitized cells to cabergoline.
• DEPTOR knockdown promoted proliferation and cabergoline resistance.
• DEPTOR inhibited both mTORC1 and mTORC2 activities.
• DEPTOR expression increased in response to cabergoline, suppressing mTOR activity by reducing βTrCP1.
• DEPTOR enhanced autophagy-dependent cell death, increasing cabergoline sensitivity.

Conclusions:

• DEPTOR downregulation is a feature of pituitary adenomas.
• DEPTOR acts as a tumor suppressor in PAs by inhibiting mTOR signaling and promoting autophagy-dependent cell death.
• DEPTOR represents a promising therapeutic target for pituitary adenoma treatment, especially for cabergoline-resistant cases.