Profiling of Unfolded Protein Response Markers and Effect of IRE1α-specific Inhibitor in Pituitary Neuroendocrine Tumor

Abstract

Context IRE1α and PERK, which are endoplasmic reticulum (ER) membrane proteins, regulate unfolded protein response (UPR). These molecules have recently gained attention as a novel therapeutic target in secretory tumors. The roles of UPR in pituitary neuroendocrine tumors (PitNETs) are unclear. Objective To clarify UPR profiling of PitNETs and to investigate the effect of pharmacological modulation of UPR by KIRA8, a newly-developed IRE1α-specific inhibitor. Methods In 131 patients with PitNETs, we evaluated RNA expressions of UPR markers in PitNETs and their clinical phenotypes. Using GH3 cells, we examined the effects of KIRA8 and its combination with octreotide on UPR profiling, cell growth and apoptosis. Results Cytoprotective adaptive-UPR (A-UPR) markers were more increased in functioning PitNETs (FPitNETs, n = 112) than nonfunctioning PitNETs (NFPitNETs, n = 19), while there was no difference in proapoptotic terminal-UPR (T-UPR) markers. Similarly, overt somatotroph tumors (ST, acromegaly, n = 11) increased A-UPR compared with silent STs (SST, n = 10). In STs, serum IGF-1 levels were inversely correlated with Txnip mRNA expressions, a representative T-UPR marker. KIRA8 inhibited cell growth and facilitated apoptosis in GH3 cells with increased expressions of T-UPR markers, which was enhanced by the combination with octreotide. Octreotide increased mRNA expressions of Txnip and Chop, but decreased spliced Xbp1 under ER stress. Octreotide is suggested to inhibit activation of IRE1α but to reciprocally induce T-UPR under PERK. Conclusion UPR markers in FPitNETs are implicated as dominant A-UPR but blunted T-UPR. KIRA8, enhanced with octreotide, unbalances UPR, leading to anti-tumor effects. Targeting IRE1α may provide a novel strategy to treat PitNETs.