Department of Neurosciences, University of Toledo, College of Medicine and Life Science, Toledo, OH 43614, United States.
Mol Cell Endocrinol. 2013 Dec 5;381(1-2):175-87. doi: 10.1016/j.mce.2013.07.033. Epub 2013 Aug 7.
Pheochromocytoma originates from chromaffin cells in the adrenal medulla and sympathetic paraganglia. 36-53% of pheochromocytoma becomes malignant and, thereafter, resistant to conventional treatments. Pheochromocytoma also causes hyper-secretion of catecholamines that cause severe hypertension. We found that an antidepressant, tianeptine, interfered with normal life cycle of pheochromocytoma cells at its clinical doses. Treatment with tianeptine caused microtubule bundling and specific degradation of cytoplasmic dynein, a retrograde microtubule motor that mediates various microtubule-dependent processes during interphase and mitosis, in the rat pheochromocytoma PC12 cells. Tianeptine also increased the levels of pro-apoptotic proteins, slowed cell cycle progression, and increased apoptosis in PC12 cells. Importantly, tianeptine treatment decreased high K(+)-stimulated secretion of norepinephrine and chromogranin A in PC12 cells and of epinephrine in the mouse pheochromocytoma MPC cells. Our study demonstrates, for the first time, that tianeptine interferes with normal life cycle of pheochromocytoma cells.
嗜铬细胞瘤起源于肾上腺髓质和交感神经节的嗜铬细胞。36-53%的嗜铬细胞瘤会发生恶性转化，从而对常规治疗产生耐药性。嗜铬细胞瘤还会导致儿茶酚胺的过度分泌，从而引起严重的高血压。我们发现，一种抗抑郁药——噻奈普汀在其临床剂量下会干扰嗜铬细胞瘤细胞的正常生命周期。在大鼠嗜铬细胞瘤 PC12 细胞中，噻奈普汀处理会导致微管束集，并特异性降解细胞质动力蛋白，这是一种逆行微管动力蛋白，在有丝分裂间期和有丝分裂过程中调节各种微管依赖的过程。噻奈普汀还增加了促凋亡蛋白的水平，减缓了 PC12 细胞的细胞周期进程，并增加了细胞凋亡。重要的是，噻奈普汀处理降低了高 K+刺激的 PC12 细胞中去甲肾上腺素和嗜铬粒蛋白 A 的分泌，以及 MPC 细胞中肾上腺素的分泌。我们的研究首次表明，噻奈普汀会干扰嗜铬细胞瘤细胞的正常生命周期。
