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Alpha-lipoic acid (ALA) has been shown to modulate cell death via PI3K/Akt signal pathway in various cells. In the present study, the effects of ALA on cell death and PI3K/Akt signal pathway linked to cell death-related proteins during endoplasmic reticulum (ER) stress in FRTL5 thyroid cells were evaluated. In FRTL5 thyroid cells, cell viability increased by ALA pretreatment in tunicamycin (TN)-treated cells. When TN was treated, CCAAT/enhancer-binding protein-homologous protein (CHOP) and Bax protein levels were elevated while Bcl-2 protein levels were reduced. ALA diminished CHOP and Bax protein levels, and augmented Bcl-2 protein levels in TN-treated cells. After exposure to TN, phospho-Akt protein levels were repressed whereas total Akt protein levels were not changed. ALA increased phospho-Akt protein levels but not total Akt protein levels in both non-TN-treated and TN-treated cells. After LY294002 administration in non-TN-treated cells, cell viability was reduced, and CHOP and Bax protein levels were elevated, and Bcl-2 protein levels were reduced. The CHOP, Bcl-2 and Bax protein levels were not different after LY294002 administration in TN-treated cells. LY294002 and wortmannin decreased cell viability, and increased CHOP and Bax protein levels, and decreased Bcl-2 protein levels in ALA-pretreated and TN-treated cells. In conclusion, these results suggest that ER stress may induce cell death by modulating PI3K/Akt signal pathway linked to cell death-related proteins in FRTL5 thyroid cells. Moreover, these findings imply that ALA may ameliorate ER stress-induced cell death by activating PI3K/Akt signal pathway and attenuating changes of cell death-related proteins in FRTL5 thyroid cells.

In thyroid cells, the effects of all- TRANS retinoic acid (ATRA) on sodium/iodide symporter (NIS) and CCAAT/enhancer-binding protein-homologous protein (CHOP) under condition of endoplasmic reticulum (ER) stress have not been evaluated. In the present study, the relationships between NIS, CHOP, and p38 MAPK, and the effects of ATRA on NIS and CHOP expression as well as on p38 MAPK activation under condition of ER stress in thyroid cells were investigated. In FRTL5 thyroid cells, NIS mRNA and protein levels decreased following tunicamycin (TN) treatment, while CHOP mRNA and protein levels increased. In addition, while CHOP mRNA levels decreased after administration of tauro-UDCA and siCHOP, NIS mRNA levels were not altered. After pretreatment with SB203580, NIS mRNA levels decreased in non-TN-treated cells but increased in TN-treated cells. In contrast, CHOP mRNA levels decreased in both non-TN-treated and TN-treated cells. Exposure to ATRA decreased NIS mRNA levels in non-TN-treated cells but increased NIS mRNA levels in TN-treated cells. ATRA decreased CHOP mRNA levels in both non-TN-treated and TN-treated cells although the response was significant only in TN-treated cells. Phospho-p38 MAPK protein levels but not total p38 MAPK protein levels increased in TN-treated cells. ATRA attenuated this increase in phopho-p38 MAPK protein levels. In conclusion, our results demonstrate that ER stress may induce reciprocal changes in NIS and CHOP expression via p38 MAPK in FRTL5 thyroid cells, and that ATRA may attenuate ER stress-induced alterations in NIS and CHOP expression by modulating the phosphorylation of p38 MAPK in FRTL5 thyroid cells.