%0 Journal Article
%T Lithium Improves Survival of PC12 Pheochromocytoma Cells in High-Density Cultures and after Exposure to Toxic Compounds
%A Cinzia Fabrizi
%A Stefania De Vito
%A Francesca Somma
%A Elena Pompili
%A Angela Catizone
%A Stefano Leone
%A Paola Lenzi
%A Francesco Fornai
%A Lorenzo Fumagalli
%J International Journal of Cell Biology
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/135908
%X Autophagy is an evolutionary conserved mechanism that allows for the degradation of long-lived proteins and entire organelles which are driven to lysosomes for digestion. Different kinds of stressful conditions such as starvation are able to induce autophagy. Lithium and rapamycin are potent autophagy inducers with different molecular targets. Lithium stimulates autophagy by decreasing the intracellular myo-inositol-1,4,5-triphosphate levels, while rapamycin acts through the inhibition of the mammalian target of rapamycin (mTOR). The correlation between autophagy and cell death is still a matter of debate especially in transformed cells. In fact, the execution of autophagy can protect cells from death by promptly removing damaged organelles such as mitochondria. Nevertheless, an excessive use of the autophagic machinery can drive cells to death via a sort of self-cannibalism. Our data show that lithium (used within its therapeutic window) stimulates the overgrowth of the rat Pheochromocytoma cell line PC12. Besides, lithium and rapamycin protect PC12 cells from toxic compounds such as thapsigargin and trimethyltin. Taken together these data indicate that pharmacological activation of autophagy allows for the survival of Pheochromocytoma cells in stressful conditions such as high-density cultures and exposure to toxins. 1. Introduction Pheochromocytoma is a rare neuroendocrine tumour derived from chromaffin cells of the adrenal gland. Surgical resection of the tumour is the treatment of choice and usually results in cure of the hypertension related to the excessive release of catecholamines. Approximately, 17% of these tumours are malignant and treatment for metastatic disease includes surgical resection and chemotherapy with nonspecific agents which indiscriminately target dividing cells [1]. A previous report indicates a possible novel strategy for treatment of Pheochromocytomas and paragangliomas showing that lithium determines a net reduction of the growth in culture of the rat Pheochromocytoma cell line PC12 [2]. Lithium is already therapeutically widely used as a mood stabilizer in the treatment of bipolar disorders and in human patients levels of lithium in the serum are kept in the range of 0.4¨C1.2£żmM [3]. Due to its diverse molecular targets, the action of lithium may be complex and the interpretation of its effects in biological systems is often controversial. In fact, lithium is a monovalent cation with different cellular targets depending on its concentration. At 0.5¨C1£żmM it acts mainly as an inhibitor of inositol monophosphatase (IMPase) (Ki
%U http://www.hindawi.com/journals/ijcb/2014/135908/