Pituitary tumors (PTs) represent about 10% of all intracranial tumors, and most are benign. However, some PTs exhibit continued growth despite multimodal therapies. Although temozolomide (TMZ), an alkylating chemotherapeutic agent, is a first-line medical treatment for aggressive PTs, some PTs are resistant to TMZ. Existing literature indicated the involvement of autophagy in cell growth in several types of tumors, including PTs, and autophagy inhibitors have anti-tumor effects. In this study, the expression of several autophagy-inducible genes, including , , , in two PT cell lines, the mouse corticotroph AtT-20 cells and the rat mammosomatotroph GH4 cells were identified. Down regulation of , a master switch of basal autophagy, using RNA interference, suppressed cell proliferation in AtT-20 cells, suggesting basal autophagy contributes to the maintenance of cellular functions in PT cells. Expectedly, treatment with bafilomycin A1, an autophagy inhibitor, suppressed cell proliferation, increased the cleavage of PARP1, and reduced ACTH production in AtT-20 cells. Treatment with two additional autophagy inhibitors, chloroquine (CQ) and monensin, demonstrated similar effects on cell proliferation, apoptosis, and ACTH production in AtT-20 cells. Also, treatment with CQ suppressed cell proliferation and growth hormone production in GH4 cells. Moreover, the combination of CQ and TMZ had an additive effect on the inhibition of cell proliferation in AtT-20 and GH4 cells. The additive effect of anti-cancer drugs such as CQ alone or in combination with TMZ may represent a novel therapeutic approach for PTs, in particular tumors with resistance to TMZ.

中文翻译：

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自噬抑制可抑制垂体肿瘤细胞的激素产生和细胞生长：治疗垂体肿瘤的潜在方法

垂体瘤 (PT) 约占所有颅内肿瘤的 10%，大多数是良性的。然而，尽管采用多模式治疗，一些 PT 仍表现出持续增长。尽管替莫唑胺 (TMZ)（一种烷化化疗剂）是治疗侵袭性 PT 的一线药物，但一些 PT 对 TMZ 具有耐药性。现有文献表明自噬参与包括PT在内的多种类型肿瘤的细胞生长，自噬抑制剂具有抗肿瘤作用。在本研究中，鉴定了几种自噬诱导基因的表达，包括 、 、 、 在两种 PT 细胞系（小鼠促皮质细胞 AtT-20 细胞和大鼠促乳腺细胞 GH4 细胞）中的表达。使用RNA干扰下调基础自噬的主开关，可抑制AtT-20细胞的细胞增殖，表明基础自噬有助于维持PT细胞的细胞功能。预计，用自噬抑制剂巴弗洛霉素 A1 治疗可抑制 AtT-20 细胞中的细胞增殖、增加 PARP1 的裂解并减少 ACTH 的产生。使用另外两种自噬抑制剂氯喹 (CQ) 和莫能菌素治疗，对 AtT-20 细胞中的细胞增殖、凋亡和 ACTH 产生具有类似的影响。此外，CQ 处理抑制了 GH4 细胞的细胞增殖和生长激素的产生。此外，CQ和TMZ的组合对AtT-20和GH4细胞的细胞增殖抑制具有相加作用。单独使用 CQ 或与 TMZ 联合使用等抗癌药物的累加效应可能代表一种新的 PT 治疗方法，特别是对 TMZ 耐药的肿瘤。