Tianeptine interferes with microtubule organization and hormone secretion of pheochromocytoma cells.
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.
Department of Neurosciences, University of Toledo, College of Medicine and Life Science, Toledo, OH 43614, United States.
Vishruti
V
Makani
James
J
Hall
Khola
K
Qamar
Priyanka
P
Jain
Yonggil
Y
Jang
Kenneth
K
Hensley
Joshua J
JJ
Park
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D053379:Chromogranin A / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000188:drug therapy*; D055503:Protein Multimerization / Q000187:drug effects; D055550:Protein Stability; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*
D000970:Antineoplastic Agents; D053379:Chromogranin A; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D013841:Thiazepines; D050257:Tubulin Modulators; C050504:tianeptine; D004398:Dyneins; D009638:Norepinephrine
Cytoplasmic dynein; Microtubule bundling; Pheochromocytoma; Tianeptine