Lithium Improves Survival of PC12 Pheochromocytoma Cells in High-Density Cultures and after Exposure to Toxic Compounds

Abstract

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.

Autophagy in endocrine tumors

“…Unlike RGZ-induced autophagy in adrenocortical carcinoma cells, however, current research suggests that chemically induced autophagy in the rat pheochromocytoma cell line, PC12, promotes cell survival (Ikeda et al 2013, Fabrizi et al 2014. For example, sunitinib, a known anticancer drug, induces both apoptosis and autophagy in PC12 cells, most likely through the direct inhibition of mTOR (Saito et al 2012, Ikeda et al 2013.…”

“…Although lithium was also proposed as a treatment option for pheochromocytomas due to its ability to inhibit PC12 cell growth in culture (Kappes et al 2007), the doses used in that paper were well outside the established therapeutic window for lithium use. When given in dosages within its therapeutic window, lithium promoted the proliferation of PC12 cells in culture and protected them from toxin-induced cell death (Fabrizi et al 2014). Moreover, the protective effect of lithium seemed to be mediated through its induction of autophagy as a mechanism to cope with cell stress in response to a lack of nutrients due to overgrowth, as well as toxic compounds (Fabrizi et al 2014).…”

“…When given in dosages within its therapeutic window, lithium promoted the proliferation of PC12 cells in culture and protected them from toxin-induced cell death (Fabrizi et al 2014). Moreover, the protective effect of lithium seemed to be mediated through its induction of autophagy as a mechanism to cope with cell stress in response to a lack of nutrients due to overgrowth, as well as toxic compounds (Fabrizi et al 2014). This discrepancy between the findings of Kappes et al (2007) and Fabrizi et al (2014) may be indicative of the fine line between autophagy as a protective mechanism and overstimulation of autophagy leading to programmed cell death.…”

“…Moreover, the protective effect of lithium seemed to be mediated through its induction of autophagy as a mechanism to cope with cell stress in response to a lack of nutrients due to overgrowth, as well as toxic compounds (Fabrizi et al 2014). This discrepancy between the findings of Kappes et al (2007) and Fabrizi et al (2014) may be indicative of the fine line between autophagy as a protective mechanism and overstimulation of autophagy leading to programmed cell death. Due to its propensity for activating autophagy as a defense mechanism at therapeutically viable doses, contrary to the suggestion of Kappes et al (2007), the use of lithium as a treatment for pheochromocytomas is unlikely to be effective.…”

“…In the treatment of one adrenocortical carcinoma cell line, RGZ appears to exert its anticancer effects via the induction of autophagy (Cerquetti et al 2011). In the treatment of pheochromocytomas, however, autophagy acts as a protective mechanism for the PC12 cells in the face of cytotoxic treatments (Ikeda et al 2013, Fabrizi et al 2014. Even between two different cell lines of one subtype of adrenal cancer autophagy is differentially involved in treatment mechanism.…”