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BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Prostate Cancer | Research article

Salinomycin triggers endoplasmic reticulum stress through ATP2A3 upregulation in PC-3 cells

Authors: Yunsheng Zhang, Fang Li, Luogen Liu, Hongtao Jiang, Hua Hu, Xiaobo Du, Xin Ge, Jingsong Cao, Yi Wang

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

Salinomycin is a monocarboxylic polyether antibiotic and is a potential chemotherapy drug. Our previous studies showed that salinomycin inhibited cell growth and targeted CSCs in prostate cancer. However, the precise target of salinomycin action is unclear.

Methods

In this work, we analyzed and identified differentially expressed genes (DEGs) after treatment with or without salinomycin using a gene expression microarray in vitro (PC-3 cells) and in vivo (NOD/SCID mice xenograft model generated from implanted PC-3 cells). Western blotting and immunohistochemical staining were used to analyze the expression of ATP2A3 and endoplasmic reticulum (ER) stress biomarkers. Flow cytometry was used to analyze the cell cycle, apoptosis and intracellular Ca2+ concentration.

Results

A significantly upregulated gene, ATPase sarcoplasmatic/endoplasmatic reticulum Ca2+ transporting 3 (ATP2A3), was successfully identified. In subsequent studies, we found that ATP2A3 overexpression could trigger ER stress and exert anti-cancer effects in PC-3 and DU145 cells. ATP2A3 was slightly expressed, but the ER stress biomarkers showed strong staining in prostate cancer tissues. We also found that salinomycin could trigger ER stress, which might be related to ATP2A3-mediated Ca2+ release in PC-3 cells. Furthermore, we found that salinomycin-triggered ER stress could promote apoptosis and thus exert anti-cancer effects in prostate cancer cells.

Conclusion

This study demonstrates that ATP2A3 might be one of the potential targets for salinomycin, which can inhibit Ca2+ release and trigger ER stress to exert anti-cancer effects.
Literature
1.
Dai X, Liu L, Liang Z, Guo K, Xu S, Wang H. Silencing of lncRNA MALAT1 inhibits cell cycle progression via androgen receptor signaling in prostate cancer cells. Pathol Res Pract. 2019.
2.
Sartor O. Advanced prostate cancer update 2018. Asia Pac J Clin Oncol. 2018;14 Suppl 5:9–12.CrossRef
3.
Naujokat C, Fuchs D, Opelz G. Salinomycin in cancer: a new mission for an old agent. Mol Med Rep. 2010;3(4):555–9.CrossRef
4.
Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–59.CrossRef
5.
Zhang Y, Liu L, Li F, Wu T, Jiang H, Jiang X, Du X, Wang Y. Salinomycin exerts anticancer effects on PC-3 cells and PC-3-derived Cancer stem cells in vitro and in vivo. Biomed Res Int. 2017;2017:13.
6.
Mitani M, Yamanishi T, Miyazaki Y. Salinomycin: a new monovalent cation ionophore. Biochem Biophys Res Commun. 1975;66(4):1231–6.CrossRef
7.
Zhou J, Li P, Xue X, He S, Kuang Y, Zhao H, Chen S, Zhi Q, Guo X: Salinomycin induces apoptosis in cisplatin-resistant colorectal cancer cells by accumulation of reactive oxygen species. Toxicol Lett 2013, 222(2):139–145.CrossRef
8.
Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA. Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci U S A. 2011;108(32):13253–7.CrossRef
9.
Mao J, Fan S, Ma W, Fan P, Wang B, Zhang J, Wang H, Tang B, Zhang Q, Yu X, et al. Roles of Wnt/beta-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death Dis. 2014;5:e1039.CrossRef
10.
Meng S, Wu H, Wang L, Zhang B, Bai L. Enhancement of antibiotic productions by engineered nitrate utilization in actinomycetes. Appl Microbiol Biotechnol. 2017;101(13):5341–52.CrossRef
11.
Ketola K, Hilvo M, Hyotylainen T, Vuoristo A, Ruskeepaa AL, Oresic M, Kallioniemi O, Iljin K. Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress. Br J Cancer. 2012;106(1):99–106.CrossRef
12.
Li T, Su L, Zhong N, Hao X, Zhong D, Singhal S, Liu X. Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells. Autophagy. 2013;9(7):1057–68.CrossRef
13.
Jangamreddy JR, Jain MV, Hallbeck AL, Roberg K, Lotfi K, Los MJ. Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death. Oncotarget. 2015;6(12):10134–45.CrossRef
14.
Li T, Liu X, Shen Q, Yang W, Huo Z, Liu Q, Jiao H, Chen J. Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis. Oncotarget. 2016;7(18):26580–92.PubMedPubMedCentral
15.
Zhang C, Lu Y, Li Q, Mao J, Hou Z, Yu X, Fan S, Li J, Gao T, Yan B, et al. Salinomycin suppresses TGF-beta1-induced epithelial-to-mesenchymal transition in MCF-7 human breast cancer cells. Chem Biol Interact. 2016;248:74–81.CrossRef
16.
He L, Wang F, Dai WQ, Wu D, Lin CL, Wu SM, Cheng P, Zhang Y, Shen M, Wang CF, et al. Mechanism of action of salinomycin on growth and migration in pancreatic cancer cell lines. Pancreatology. 2013;13(1):72–8.CrossRef
17.
Wu D, Zhang Y, Huang J, Fan Z, Shi F, Wang S. Salinomycin inhibits proliferation and induces apoptosis of human nasopharyngeal carcinoma cell in vitro and suppresses tumor growth in vivo. Biochem Biophys Res Commun. 2014;443(2):712–7.CrossRef
18.
Wang Y. Effects of salinomycin on cancer stem cell in human lung adenocarcinoma A549 cells. Med Chem. 2011;7(2):106–11.CrossRef
19.
Zhang Y, Li F, Liu L, Jiang H, Jiang X, Ge X, Cao J, Wang Z, Zhang L, Wang Y. Salinomycin-induced autophagy blocks apoptosis via the ATG3/AKT/mTOR signaling axis in PC-3 cells. Life Sci. 2018;207:451–60.CrossRef
20.
Ravier MA, Daro D, Roma LP, Jonas JC, Cheng-Xue R, Schuit FC, Gilon P. Mechanisms of control of the free Ca2+ concentration in the endoplasmic reticulum of mouse pancreatic beta-cells: interplay with cell metabolism and [Ca2+]c and role of SERCA2b and SERCA3. Diabetes. 2011;60(10):2533–45.CrossRef
21.
Bublitz M, Musgaard M, Poulsen H, Thogersen L, Olesen C, Schiott B, Morth JP, Moller JV, Nissen P. Ion pathways in the sarcoplasmic reticulum Ca2+−ATPase. J Biol Chem. 2013;288(15):10759–65.CrossRef
22.
Griffin JB, Rodriguez-Melendez R, Dode L, Wuytack F, Zempleni J. Biotin supplementation decreases the expression of the SERCA3 gene (ATP2A3) in Jurkat cells, thus, triggering unfolded protein response. J Nutr Biochem. 2006;17(4):272–81.CrossRef
23.
Krizanova O, Markova J, Pacak K, Skultety L, Soltysova A, Hudecova S. Triptolide induces apoptosis through the SERCA 3 upregulation in PC12 cells. Gen Physiol Biophys. 2014;33(1):137–44.CrossRef
24.
Teng Y, Ren MQ, Cheney R, Sharma S, Cowell JK. Inactivation of the WASF3 gene in prostate cancer cells leads to suppression of tumorigenicity and metastases. Br J Cancer. 2010;103(7):1066–75.CrossRef
25.
Davis JE, Xie X, Guo J, Huang W, Chu WM, Huang S, Teng Y, Wu G. ARF1 promotes prostate tumorigenesis via targeting oncogenic MAPK signaling. Oncotarget. 2016;7(26):39834–45.CrossRef
26.
Zhang Y, Yang L, Lin Y, Rong Z, Liu X, Li D. SPATA12 and its possible role in DNA damage induced by ultraviolet-C. PLoS One. 2013;8(10):e78201.CrossRef
27.
Zhang Y, Wu X, Li Y, Zhang H, Li Z, Zhang L, Ju J, Liu X, Chen X, Glybochko PV, et al. Endothelial to mesenchymal transition contributes to arsenic-trioxide-induced cardiac fibrosis. Sci Rep. 2016;6:33787.CrossRef
28.
Cardozo AK, Ortis F, Storling J, Feng YM, Rasschaert J, Tonnesen M, Van Eylen F, Mandrup-Poulsen T, Herchuelz A, Eizirik DL. Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. Diabetes. 2005;54(2):452–61.CrossRef
29.
Guo W, Diao Z, Liu W. Asymmetric dimethylarginine downregulates sarco/endoplasmic reticulum calciumATPase 3 and induces endoplasmic reticulum stress in human umbilical vein endothelial cells. Mol Med Rep. 2017;16(5):7541–7.CrossRef
30.
Monaco S, Rusciano M, Maione A, Soprano M, Gomathinayagam R, Todd L, Campiglia P, Salzano S, Pastore L, Leggiero E, et al. A novel crosstalk between calcium/calmodulin kinases II and IV regulates cell proliferation in myeloid leukemia cells. Cell Signal. 2015;27(2):204–14.CrossRef
31.
Nakanishi A, Hatano N, Fujiwara Y, Bin Shari A, Takabatake S, Akano H, Kanayama N, Magari M, Nozaki N, Tokumitsu H. AMP-activated protein kinase-mediated feedback phosphorylation controls the Ca2+/calmodulin (CaM) dependence of Ca2+/CaM-dependent protein kinase kinase beta. J Biol Chem. 2017.
32.
Wei XH, Yu SD, Ren L, Huang SH, Yang QM, Wang P, Chu YP, Yang W, Ding YS, Huo Y, et al. Inhibition of late sodium current suppresses calcium-related ventricular arrhythmias by reducing the phosphorylation of CaMK-II and sodium channel expressions. Sci Rep. 2017;7(1):981.CrossRef
33.
Menconi MJ, Wei W, Yang H, Wray CJ, Hasselgren PO. Treatment of cultured myotubes with the calcium ionophore A23187 increases proteasome activity via a CaMK II-caspase-calpain-dependent mechanism. Surgery. 2004;136(2):135–42.CrossRef
34.
Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012.
35.
Zhou S, Wang F, Wong ET, Fonkem E, Hsieh TC, Wu JM, Wu E. Salinomycin: a novel anti-cancer agent with known anti-coccidial activities. Curr Med Chem. 2013;20(33):4095–101.CrossRef
36.
Manago A, Leanza L, Carraretto L, Sassi N, Grancara S, Quintana-Cabrera R, Trimarco V, Toninello A, Scorrano L, Trentin L, et al. Early effects of the antineoplastic agent salinomycin on mitochondrial function. Cell Death Dis. 2015;6:e1930.CrossRef
37.
Kovacs T, Felfoldi F, Papp B, Paszty K, Bredoux R, Enyedi A, Enouf J. All three splice variants of the human sarco/endoplasmic reticulum Ca2+−ATPase 3 gene are translated to proteins: a study of their co-expression in platelets and lymphoid cells. Biochem J. 2001;358(Pt 3:559–68.CrossRef
38.
Martin V, Bredoux R, Corvazier E, Van Gorp R, Kovacs T, Gelebart P, Enouf J. Three novel sarco/endoplasmic reticulum Ca2+−ATPase (SERCA) 3 isoforms. Expression, regulation, and function of the membranes of the SERCA3 family. J Biol Chem. 2002;277(27):24442–52.CrossRef
39.
Yu SN, Kim SH, Kim KY, Ji JH, Seo YK, Yu HS, Ahn SC. Salinomycin induces endoplasmic reticulum stressmediated autophagy and apoptosis through generation of reactive oxygen species in human glioma U87MG cells. Oncol Rep. 2017;37(6):3321–8.CrossRef
40.
Guo ZY, Zhang YH, Xie GQ, Liu CX, Zhou R, Shi W. Down-regulation of Homer1 attenuates t-BHP-induced oxidative stress through regulating calcium homeostasis and ER stress in brain endothelial cells. Biochem Biophys Res Commun. 2016.
41.
Bai X, Liu S, Yuan L, Xie Y, Li T, Wang L, Wang X, Zhang T, Qin S, Song G, et al. Hydrogen-rich saline mediates neuroprotection through the regulation of endoplasmic reticulum stress and autophagy under hypoxia-ischemia neonatal brain injury in mice. Brain Res. 2016.
42.
Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89–102.CrossRef
43.
Gotoh T, Mori M. Nitric oxide and endoplasmic reticulum stress. Arterioscler Thromb Vasc Biol. 2006;26(7):1439–46.CrossRef
44.
Izquierdo-Torres E, Rodriguez G, Meneses-Morales I, Zarain-Herzberg A. ATP2A3 gene as an important player for resveratrol anticancer activity in breast cancer cells. Mol Carcinog. 2017;56(7):1703–11.CrossRef
45.
Izquierdo-Torres E, Rodríguez G, Meneses-Morales I, Zarain-Herzberg A. ATP2A3 gene as an important player for resveratrol anticancer activity in breast cancer cells. Mol Carcinog. 2017.
46.
Brini M, Carafoli E. Calcium pumps in health and disease. Physiol Rev. 2009;89(4):1341–78.CrossRef
Metadata
Title
Salinomycin triggers endoplasmic reticulum stress through ATP2A3 upregulation in PC-3 cells
Authors
Yunsheng Zhang
Fang Li
Luogen Liu
Hongtao Jiang
Hua Hu
Xiaobo Du
Xin Ge
Jingsong Cao
Yi Wang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5590-8

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