Objective Thapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown. Methods In this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells. Results The results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG. Conclusion Our findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.

Background: Both subacute thyroiditis (SAT) and Graves' disease (GD) can lead to thyrotoxicosis, but the methods to distinguish these two diseases are relatively complex. Therefore, it is necessary to find biomarkers which can quickly and efficiently identify the two kinds of thyrotoxicosis. Blood cell-derived indexes are widely used to evaluate systemic inflammation. We aimed to evaluate the diagnostic value of blood cellderived indexes in SAT patients with thyrotoxicosis.Methods: Totally 139 SAT patients with thyrotoxicosis, 146 GD patients, and 100 euthyroid individuals were enrolled in the study. Complete blood cell (CBC) count, thyroid function, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), systemic immuneinflammatory index (SII), systemic inflammation response index (SIRI), aggregate inflammation systemic index (AISI), and mean platelet volume to platelet ratio (MPR) were evaluated in all subjects. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the capacity of blood cell-derived indexes in differentiating SAT patients with thyrotoxicosis from GD patients. We also evaluated the association between blood cell-derived indexes and other laboratory indicators and clinical outcomes in SAT patients.Results: NLR, PLR, MLR, SII, SIRI, and AISI were significantly higher in the SAT group. MPR was significantly lower in the SAT group. A formula including NLR, PLR, MLR, SII, SIRI, AISI and MPR was developed. The combination formula with an optimal cutoff of 0.426 showed the better diagnostic value [area under the curve (AUC) =0.921; 95% confidence interval (CI): 0.891-0.950; P<0.001; sensitivity, 87.1%; specificity, 83.6%]. However, thyroid function, erythrocyte sedimentation rate (ESR), thyroid peroxidase antibodies (TPOAb), and blood cell-derived indexes, were not found to be significantly associated with hypothyroidism and recurrence. Conclusions:We developed a formula combining 7 blood cell-derived indexes. The combination formula could be a novel biomarker to distinguish SAT patients with thyrotoxicosis from GD patients. However, we did not find significant association between the blood cell-derived indexes and clinical outcomes in SAT patients.

Adrenocortical carcinoma (ACC) is an invasive tumor that occurs in the endocrine system. Increasing evidence has shown that endoplasmic reticulum (ER) stress and autophagy play an important role in tumor formation. Tauroursodeoxycholic acid (TUDCA) is an ER chemical chaperone that can alleviate ER stress. In the present study, TUDCA promoted the proliferation, migration and invasion of ACC SW-13 and NCI-H295R cells. Reverse transcription-quantitative PCR and western blot analysis showed that the expression of glucose-regulated protein 78, a promoter of ER stress, was decreased. The expression levels of protein kinase R (PKR)-like ER kinase and activating transcription factor 6 were correspondingly decreased, and the downstream proteins, C/EBP homologous protein and JNK, were also decreased. The expression levels of the autophagy factor microtubule-associated protein light chain 3-II/I and the anti-apoptotic factor Bcl-2 increased following TUDCA treatment, while the expression of the pro-apoptotic factor Bax decreased. TUDCA alleviated ER stress in ACC SW-13 and NCI-H295R cells and induced autophagy, thereby inhibiting ACC cell apoptosis. ER stress- and autophagy-related signaling pathways are involved in the occurrence of ACC, which may provide potential therapeutic targets for ACC treatment.