Tauroursodeoxycholic acid mediates endoplasmic reticulum stress and autophagy in adrenocortical carcinoma cells

Huang,Xuemei; Wu,Lili; Kuang,Yaqi; Li,Xin; Deng,Xiujun; Liang,Xinghuan; Li,Li; Yang,Haiyan; Huang,Zhenxing; Lu,Decheng; Luo,Zuojie

doi:10.3892/ol.2019.11057

Tauroursodeoxycholic acid mediates endoplasmic reticulum stress and autophagy in adrenocortical carcinoma cells

Authors:
- Xuemei Huang
- Lili Wu
- Yaqi Kuang
- Xin Li
- Xiujun Deng
- Xinghuan Liang
- Li Li
- Haiyan Yang
- Zhenxing Huang
- Decheng Lu
- Zuojie Luo
View Affiliations

Affiliations: Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China, Department of Integrated Medicine, The Affiliated Tumour Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: November 5, 2019 https://doi.org/10.3892/ol.2019.11057
Pages: 6475-6482
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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.

View Figures

View References

1	Xie C, Tanakchi S, Raygada M, Davis JL and Del Rivero J: Case report of an adrenocortical carcinoma associated with germline CHEK2 mutation. J Endocr Soc. 3:284–290. 2018. View Article : Google Scholar : PubMed/NCBI
2	Xiao H, Xu D, Chen P, Zeng G, Wang X and Zhang X: Identification of five genes as a potential biomarker for predicting progress and prognosis in adrenocortical carcinoma. J Cancer. 9:4484–4495. 2018. View Article : Google Scholar : PubMed/NCBI
3	Li Y, Bian X, Ouyang J, Wei S, He M and Luo Z: Nomograms to predict overall survival and cancer-specific survival in patients with adrenocortical carcinoma. Cancer Manag Res. 10:6949–6959. 2018. View Article : Google Scholar : PubMed/NCBI
4	Else T, Kim AC, Sabolch A, Raymond VM, Kandathil A, Caoili EM, Jolly S, Miller BS, Giordano TJ and Hammer GD: Adrenocortical carcinoma. Endocr Rev. 35:282–326. 2014. View Article : Google Scholar : PubMed/NCBI
5	Gonzalez RJ, Tamm EP, Ng C, Phan AT, Vassilopoulou-Sellin R, Perrier ND, Evans DB and Lee JE: Response to mitotane predicts outcome in patients with recurrent adrenal cortical carcinoma. Surgery. 142:867–875. 2007. View Article : Google Scholar : PubMed/NCBI
6	Schteingart DE, Doherty GM, Gauger PG, Giordano TJ, Hammer GD, Korobkin M and Worden FP: Management of patients with adrenal cancer: Recommendations of an international consensus conference. Endocrine-Related Cancer. 12:667–680. 2005. View Article : Google Scholar : PubMed/NCBI
7	Mohan DR, Lerario AM and Hammer GD: Therapeutic targets for adrenocortical carcinoma in the genomics era. J Endocr Soc. 2:1259–1274. 2018. View Article : Google Scholar : PubMed/NCBI
8	Baudin E; Endocrine Tumor Board of Gustave R, : Adrenocortical carcinoma. Endocrinol Metab Clin North Am. 44:411–434. 2015. View Article : Google Scholar : PubMed/NCBI
9	Teng Y, Zhao H, Gao L, Zhang W, Shull AY and Shay C: FGF19 protects hepatocellular carcinoma cells against endoplasmic reticulum stress via activation of FGFR4- GSK3β-Nrf2 Signaling. Cancer Res. 77:6215–6225. 2017. View Article : Google Scholar : PubMed/NCBI
10	Kim C and Kim B: Anti-cancer natural products and their bioactive compounds inducing ER stress-mediated apoptosis: A review. Nutrients. 10(pii): E10212018. View Article : Google Scholar : PubMed/NCBI
11	Limonta P, Moretti RM, Marzagalli M, Fontana F, Raimondi M and Montagnani Marelli M: Role of endoplasmic reticulum stress in the anticancer activity of natural compounds. Int J Mol Sci. 20(pii): E9612019. View Article : Google Scholar : PubMed/NCBI
12	Wang M, Law ME, Castellano RK and Law BK: The unfolded protein response as a target for anticancer therapeutics. Crit Rev Oncol Hematol. 127:66–79. 2018. View Article : Google Scholar : PubMed/NCBI
13	Moon HW, Han HG and Jeon YJ: Protein quality control in the endoplasmic reticulum and cancer. Int J Mol Sci. 19(pii): E30202018. View Article : Google Scholar : PubMed/NCBI
14	Zhou F, Yang X, Zhao H, Liu Y, Feng Y, An R, Lv X, Li J and Chen B: Down-regulation of OGT promotes cisplatin resistance by inducing autophagy in ovarian cancer. Theranostics. 8:5200–5212. 2018. View Article : Google Scholar : PubMed/NCBI
15	Li S, Guo L, Qian P, Zhao Y, Liu A, Ji F, Chen L, Wu X and Qian G: Lipopolysaccharide induces autophagic cell death through the PERK-dependent branch of the unfolded protein response in human alveolar epithelial A549 cells. Cell Physiol Biochem. 36:2403–2417. 2015. View Article : Google Scholar : PubMed/NCBI
16	Luchetti F, Crinelli R, Cesarini E, Canonico B, Guidi L, Zerbinati C, Di Sario G, Zamai L, Magnani M, Papa S and Iuliano L: Endothelial cells, endoplasmic reticulum stress and oxysterols. Redox Biol. 13:581–587. 2017. View Article : Google Scholar : PubMed/NCBI
17	Chen Y, Liu CP, Xu KF, Mao XD, Lu YB, Fang L, Yang JW and Liu C: Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes. Am J Nephrol. 28:1014–1022. 2008. View Article : Google Scholar : PubMed/NCBI
18	Yang Y, Tang X, Hao F, Ma Z, Wang Y, Wang L and Gao Y: Bavachin induces apoptosis through mitochondrial regulated ER stress pathway in HepG2 cells. Biol Pharm Bull. 41:198–207. 2018. View Article : Google Scholar : PubMed/NCBI
19	Guo Q, Shi Q, Li H, Liu J, Wu S, Sun H and Zhou B: Glycolipid metabolism disorder in the liver of obese mice is improved by TUDCA via the restoration of defective hepatic autophagy. Int J Endocrinol. 2015:6879382015. View Article : Google Scholar : PubMed/NCBI
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
21	Li J, Wang Y, Ge J, Li W, Yin L, Zhao Z, Liu S, Qin H, Yang J, Wang L, et al: Doublecortin-like kinase 1 (DCLK1) regulates B cell-specific moloney murine leukemia virus insertion site 1 (Bmi-1) and is associated with metastasis and prognosis in pancreatic cancer. Cell Physiol Biochem. 51:262–277. 2018. View Article : Google Scholar : PubMed/NCBI
22	Rahman FU, Ali A, Duong HQ, Khan IU, Bhatti MZ, Li ZT, Wang H and Zhang DW: ONS-donor ligand based Pt(II) complexes display extremely high anticancer potency through autophagic cell death pathway. Eur J Med Chem. 164:546–561. 2019. View Article : Google Scholar : PubMed/NCBI
23	Vandewynckel YP, Laukens D, Devisscher L, Paridaens A, Bogaerts E, Verhelst X, Van den Bussche A, Raevens S, Van Steenkiste C, Van Troys M, et al: Tauroursodeoxycholic acid dampens oncogenic apoptosis induced by endoplasmic reticulum stress during hepatocarcinogen exposure. Oncotarget. 6:28011–28025. 2015. View Article : Google Scholar : PubMed/NCBI
24	Wu CH, Silvers CR, Messing EM and Lee YF: Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells. J Biol Chem. 294:3207–3218. 2019. View Article : Google Scholar : PubMed/NCBI
25	Luo B and Lee AS: The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies. Oncogene. 32:805–818. 2013. View Article : Google Scholar : PubMed/NCBI
26	Guzel E, Arlier S, Guzeloglu-Kayisli O, Tabak MS, Ekiz T, Semerci N, Larsen K, Schatz F, Lockwood CJ and Kayisli UA: Endoplasmic reticulum stress and homeostasis in reproductive physiology and pathology. Int J Mol Sci. 18:E7922017. View Article : Google Scholar : PubMed/NCBI
27	Liu Z, Xia Y, Li B, Xu H, Wang C, Liu Y, Li Y, Li C, Gao N and Li L: Induction of ER stress-mediated apoptosis by ceramide via disruption of ER Ca(2+) homeostasis in human adenoid cystic carcinoma cells. Cell Biosci. 4:712014. View Article : Google Scholar : PubMed/NCBI
28	Marquardt A, Al-Dabet MM, Ghosh S, Kohli S, Manoharan J, ElWakiel A, Gadi I, Bock F, Nazir S and Wang H: Farnesoid X receptor agonism protects against diabetic tubulopathy: Potential add-on therapy for diabetic nephropathy. J Am Soc Nephrol. 28:3182–3189. 2017. View Article : Google Scholar : PubMed/NCBI
29	Galluzzi L, Pietrocola F, Bravo-San Pedro JM, Amaravadi RK, Baehrecke EH, Cecconi F, Codogno P, Debnath J, Gewirtz DA, Karantza V, et al: Autophagy in malignant transformation and cancer progression. EMBO J. 34:856–880. 2015. View Article : Google Scholar : PubMed/NCBI
30	Amaravadi R, Kimmelman AC and White E: Recent insights into the function of autophagy in cancer. Genes Dev. 30:1913–1930. 2016. View Article : Google Scholar : PubMed/NCBI
31	Cotzomi-Ortega I, Aguilar-Alonso P, Reyes-Leyva J and Maycotte P: Autophagy and its role in protein secretion: Implications for cancer therapy. Mediators Inflamm. 2018:42315912018. View Article : Google Scholar : PubMed/NCBI
32	B'Chir W, Chaveroux C, Carraro V, Averous J, Maurin AC, Jousse C, Muranishi Y, Parry L, Fafournoux P and Bruhat A: Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation. Cell Signal. 26:1385–1391. 2014. View Article : Google Scholar : PubMed/NCBI
33	Lei Y, Wang S, Ren B, Wang J, Chen J, Lu J, Zhan S, Fu Y, Huang L and Tan J: CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy. PLoS One. 12:e01836802017. View Article : Google Scholar : PubMed/NCBI
34	Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N, et al: ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 129:1337–1349. 2007. View Article : Google Scholar : PubMed/NCBI
35	Cheng S, Swanson K, Eliaz I, McClintick JN, Sandusky GE and Sliva D: Pachymic acid inhibits growth and induces apoptosis of pancreatic cancer in vitro and in vivo by targeting ER stress. PLoS One. 10:e01222702015. View Article : Google Scholar : PubMed/NCBI