IndraLab

"For the first time, we showed that USP8 knockdown or gefitinib treatment significantly reduced ACTH secretion in primary USP8 mutated corticotrophin adenoma cells, but not in wild-type cells."

"USP8 knockdown leads to reduce EGFR protein and inhibits ACTH secretion."

"USP8 mutated tumors are more common in females, and are associated with earlier onset, a smaller size, and increased ACTH production."

"We further showed that USP8 knockdown or gefitinib (a clinically available EGFR inhibitor) treatment significantly reduced ACTH secretion in primary USP8 mutated corticotrophin adenoma cells, but not in wild-type cells."

"Because EGFR signaling increases POMC transcription and secretion of ACTH [XREF_BIBR], increased USP8 activity causes elevated ACTH production."

"The presence of such associations is supported by the finding that USP8 knockdown or EGFR inhibition attenuates ACTH secretion in primary USP8 mutated tumor cells [XREF_BIBR]."

"We will provide an overview of corticotroph tumorigenesis in the context of hypothalamic-pituitary-adrenal (HPA) axis regulation with an emphasis on the role of the glucocorticoid receptor in the resistance to the negative feedback of cortisol that occurs in CD, and we will explore the role of epidermal growth factor receptor (EGFR) signaling in ACTH hyper-secretion and corticotroph cell proliferation and the recent discovery of somatic ubiquitin specific peptidase 8 (USP8) mutations in a significant number of patients with sporadic CD with an emphasis on therapeutic implications."

"USP8 knockdown using shRNA in primary corticotroph adenoma cells effectively reduced ACTH production."