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 expression 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 in nonfunctioning PitNETs (NFPitNETs, n = 19), while there was no difference in proapoptotic terminal-UPR (T-UPR) markers. Similarly, overt somatotroph tumors (STs, acromegaly, n = 11) increased A-UPR compared with silent STs (n = 10). In STs, serum IGF-1 levels were inversely correlated with Txnip mRNA expression, 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 expression 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.
CONCLUSIONS: UPR markers in FPitNETs are implicated as dominant A-UPR but blunted T-UPR. KIRA8, enhanced with octreotide, unbalances the UPR, leading to antitumor effects. Targeting IRE1α may provide a novel strategy to treat PitNETs.
目的:阐明PitNETs的UPR谱,并研究新开发的IRE1α特异性抑制剂KIRA8对UPR的药理调节作用。
方法:在131例PitNET患者中,我们评估了PitNETs中UPR标记的RNA表达及其临床表型。使用GH3细胞,我们检查了KIRA8及其与奥曲肽的组合对UPR谱的影响,细胞生长和凋亡。
结果:细胞保护性适应性UPR(A-UPR)标记在功能正常的PitNET(FPitNET,n=112)比无功能的PitNET(NFPitNET,n=19),而促凋亡终末UPR(T-UPR)标记没有差异。同样,明显的生长激素肿瘤(ST,肢端肥大症,n=11)与沉默的ST相比,A-UPR增加(SST,n=10)。在ST中,血清IGF-1水平与TxnipmRNA表达呈负相关,代表性T-UPR标记。KIRA8抑制细胞生长,促进GH3细胞凋亡,增加T-UPR标志物的表达,与奥曲肽的组合增强了。奥曲肽增加Txnip和Chop的mRNA表达,但在ER应力下减少了剪接的Xbp1。建议奥曲肽抑制IRE1α的激活,但在PERK下相互诱导T-UPR。
结论:FPitNETs中的UPR标记与显性A-UPR有关,但T-UPR钝化。KIRA8,用奥曲肽增强,不平衡UPR,导致抗肿瘤作用。靶向IRE1α可以提供一种治疗PitNETs的新策略。