First Department of Internal Medicine, Wakayama Medical University, Wakayama 641-8509, Japan.
Department of Diabetes and Endocrinology, Shizuoka General Hospital, Shizuoka 420-8527, Japan.
Endocrinology. 2024 Feb 20;165(4). doi: 10.1210/endocr/bqae008.
Inositol-requiring enzyme 1α (IRE1α) and PKR-like ER kinase (PERK), which are endoplasmic reticulum (ER) membrane proteins, regulate the unfolded protein response (UPR). These molecules have recently gained attention as a novel therapeutic target in secretory tumors. The roles of the UPR in pituitary neuroendocrine tumors (PitNETs) are unclear.
To clarify UPR profiling of PitNETs and to investigate the effect of pharmacological modulation of UPR by KIRA8, a newly developed IRE1α-specific inhibitor.
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.
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.
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.
内质网（ER）膜蛋白肌醇需求酶 1α（IRE1α）和 PKR 样 ER 激酶（PERK）调节未折叠蛋白反应（UPR）。这些分子最近作为分泌性肿瘤的一种新的治疗靶点引起了关注。UPR 在垂体神经内分泌肿瘤（PitNETs）中的作用尚不清楚。
阐明 PitNETs 的 UPR 特征，并研究新型 IRE1α 特异性抑制剂 KIRA8 对 UPR 的药理学调节作用。
在 131 例 PitNETs 患者中，我们评估了 PitNETs 及其临床表型的 UPR 标志物的 RNA 表达。使用 GH3 细胞，我们研究了 KIRA8 及其与奥曲肽联合应用对 UPR 谱、细胞生长和凋亡的影响。
在功能性 PitNETs（FPitNETs，n=112）中，细胞保护性适应性 UPR（A-UPR）标志物的增加更为明显，而非功能性 PitNETs（NFPitNETs，n=19）则没有差异。促凋亡终末 UPR（T-UPR）标志物也是如此。同样，显性生长激素细胞瘤（STs，肢端肥大症，n=11）与沉默性 STs（n=10）相比，A-UPR 增加。在 STs 中，血清 IGF-1 水平与 T-UPR 标志物 Txnip mRNA 表达呈负相关。KIRA8 抑制 GH3 细胞的生长并促进其 T-UPR 标志物表达增加的细胞凋亡，与奥曲肽联合应用可增强其作用。奥曲肽在 ER 应激下增加 Txnip 和 Chop 的 mRNA 表达，但减少剪接 Xbp1 的表达。奥曲肽被认为可抑制 IRE1α 的激活，但在 PERK 下可反向诱导 T-UPR。
FPitNETs 的 UPR 标志物提示为优势 A-UPR，但 T-UPR 减弱。KIRA8 与奥曲肽联合应用可使 UPR 失衡，从而产生抗肿瘤作用。靶向 IRE1α 可能为治疗 PitNETs 提供一种新策略。
