PCSK1N as a Tumor Size Marker and an ER Stress Response Protein in Corticotroph Pituitary Adenomas

Silent corticotroph adenoma (SCA) exhibits more tumor aggressiveness features than functioning adenomas (FCAs).

We aimed to investigate proprotein convertase subtilisin/kexin type 1 inhibitor (PCSK1N) expression in CA and examine if endoplasmic reticulum (ER) stress-induced responses affect cell survival in a corticotroph tumor cell model.

Clinical and imaging characteristics were recorded in 33 patients with FCA (20 women, 11 macroadenomas) and 18 SCAs (8 women, all macroadenomas). Gene expression of pro-opiomelanocortin (POMC), T-box transcription factor 19(TBX19)/TPIT, proprotein convertase subtilisin/kexin type 1 (PCSK1)/PC1/3, and its inhibitor PCSK1N, was measured by reverse transcription-quantitative polymerase chain reaction in adenoma tissue. Mouse pituitary corticotroph tumor (AtT-20) cells were treated with tanespimycin (17-AAG), an HSP90 chaperone inhibitor, to induce ER stress, followed by gene and protein analyses.

POMC, TPIT, and PCSK1 expression were higher, whereas PCSK1N was lower in FCA compared to SCA. PCSK1N correlated with POMC (rs = -0.514; P < .001), TPIT (rs = -0.386; P = .005), PCSK1 (rs = -0.3691; P = .008), and tumor largest diameter (rs = 0.645; P < .001), in all CA. Induction of ER stress by 17-AAG in AtT-20 cells led to a decrease of Pomc and an increase of Pcsk1n gene expression at 24 hours. Moreover, a downregulation of cell cycle, apoptosis, and senescence pathways, and alterations in cell adhesion and cytoskeleton, were observed at the protein level.

PCSK1N is higher in SCA compared with FCA, and associated with corticotroph cell markers and tumor size. PCSK1N is likely to be part of the adaptive response to ER stress, potentially conferring a survival advantage to the corticotroph tumor cell in conjunction with other proteins.