Involvement of CHOP in activin A‑induced myeloma NS‑1 cell apoptosis

Ge,Jingyan; Sun,Hongyan; Li,Jing; Shan,Yidi; Zhao,Yang; Liao,Fangwei; Yang,Yu; Cui,Xueling; Liu,Zhonghui

doi:10.3892/or.2019.7382

Involvement of CHOP in activin A‑induced myeloma NS‑1 cell apoptosis

Authors:
- Jingyan Ge
- Hongyan Sun
- Jing Li
- Yidi Shan
- Yang Zhao
- Fangwei Liao
- Yu Yang
- Xueling Cui
- Zhonghui Liu
View Affiliations

Affiliations: Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Genetics, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China, Department of Functional Laboratory, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: October 22, 2019 https://doi.org/10.3892/or.2019.7382
Pages: 2644-2654
Copyright: © Ge 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

Activin A, a multifunctional cytokine, is a member of transforming growth factor‑β (TGF‑β) superfamily. It is associated with a variety of pathophysiological processes, including inflammation, fibrosis, and tumorigenesis. Chronic or prolonged endoplasmic reticulum (ER) stress can lead to cells apoptosis. However, whether ER stress‑related proteins, such as CHOP, GADD34 are involved in activin A‑induced myeloma cell apoptosis remains unknown. In the present study, it was revealed that activin A inhibited the proliferation of myeloma cell line NS‑1 cells and induced NS‑1 cell apoptosis. Activin A upregulated the expression of CHOP, GADD34, caspase‑3, and caspase‑12. Moreover, both Smad3 and p‑Smad3 levels were increased with treatment of activin A. Further studies revealed that the overexpression of activin signaling protein Smad3 in NS‑1 cells increased the levels of CHOP, caspase‑3, and p‑Smad3. These data indicated that the CHOP protein of the ER stress pathway may be involved in activin A‑induced NS‑1 cell apoptosis, and also indicated the potential therapy of activin A‑induced apoptosis via CHOP signaling for multiple myeloma.

View Figures

View References

1	Ling N, Ying SY, Ueno N, Shimasaki S, Esch F, Hotta M and Guillemin R: Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin. Nature. 321:779–782. 1986. View Article : Google Scholar : PubMed/NCBI
2	Woodruff TK, Besecke LM, Groome N, Draper LB, Schwartz NB and Weiss J: Inhibin A and inhibin B are inversely correlated to follicle stimulating hormone, yet are discordant during the follicular phase of the rat estrous cycle, and inhibin A is expressed in a sexually dimorphic manner. Endocrinology. 137:5463–5467. 1996. View Article : Google Scholar : PubMed/NCBI
3	Thompson TB, Cook RW, Chapman SC, Jardetzky TS and Woodruff TK: Beta A versus beta B: Is it merely a matter of expression? Mol Cell Endocrinol. 225:9–17. 2004. View Article : Google Scholar : PubMed/NCBI
4	Qi Y, Ge J, Ma C, Wu N, Cui X and Liu Z: Activin A regulates activation of mouse neutrophils by Smad3 signalling. Open Biol. 7:1603422017. View Article : Google Scholar : PubMed/NCBI
5	Hoda MA, Rozsas A, Lang E, Klikovits T, Lohinai Z, Torok S, Berta J, Bendek M, Berger W, Hegedus B, et al: High circulating activin A level is associated with tumor progression and predicts poor prognosis in lung adenocarcinoma. Oncotarget. 7:13388–13399. 2016. View Article : Google Scholar : PubMed/NCBI
6	Wei Q, Liu H, Liu M, Yang C, Yang J, Liu Z and Yang P: Ramipril attenuates left ventricular remodeling by regulating the expression of activin A-follistatin in a rat model of heart failure. Sci Rep. 6:336772016. View Article : Google Scholar : PubMed/NCBI
7	Jana A, Krett NL, Guzman G, Khalid A, Ozden O, Staudacher JJ, Bauer J, Baik SH, Carroll T, Yazici C and Jung B: NFkB is essential for activin-induced colorectal cancer migration via upregulation of PI3K-MDM2 pathway. Oncotarget. 8:37377–37393. 2017. View Article : Google Scholar : PubMed/NCBI
8	Arber C, Precious SV, Cambray S, Risner-Janiczek JR, Kelly C, Noakes Z, Fjodorova M, Heuer A, Ungless MA, Rodríguez TA, et al: Activin A directs striatal projection neuron differentiation of human pluripotent stem cells. Development. 142:1375–1386. 2015. View Article : Google Scholar : PubMed/NCBI
9	de Kretser DM, O'Hehir RE, Hardy CL and Hedger MP: The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair. Mol Cell Endocrinol. 359:101–106. 2012. View Article : Google Scholar : PubMed/NCBI
10	Li N, Cui X, Ge J, Li J, Niu L, Liu H, Qi Y, Liu Z and Wang Y: Activin A inhibits activities of lipopolysaccharide-activated macrophages via TLR4, not of TLR2. Biochem Biophys Res Commun. 435:222–228. 2013. View Article : Google Scholar : PubMed/NCBI
11	Jeruss JS, Sturgis CD, Rademaker AW and Woodruff TK: Down-regulation of activin, activin receptors, and smads in high-grade breast cancer. Cancer Res. 63:3783–3790. 2003.PubMed/NCBI
12	Loomans HA and Andl CD: Intertwining of activin A and TGFβ signaling: Dual roles in cancer progression and cancer cell invasion. Cancers (Basel). 7:70–91. 2014. View Article : Google Scholar : PubMed/NCBI
13	Rutkowski DT and Kaufman RJ: A trip to the ER: Coping with stress. Trends Cell Biol. 14:20–28. 2004. View Article : Google Scholar : PubMed/NCBI
14	Tabas I and Ron D: Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 13:184–190. 2011. View Article : Google Scholar : PubMed/NCBI
15	Doyle KM, Kennedy D, Gorman AM, Gupta S, Healy SJ and Samali A: Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders. J Cell Mol Med. 15:2025–2039. 2011. View Article : Google Scholar : PubMed/NCBI
16	Catena V, Bruno T, De Nicola F, Goeman F, Pallocca M, Iezzi S, Sorino C, Cigliana G, Floridi A, Blandino G and Fanciulli M: Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells. Oncotarget. 7:70546–70558. 2016. View Article : Google Scholar : PubMed/NCBI
17	Clark AL and Urano F: Endoplasmic reticulum stress in beta cells and autoimmune diabetes. Curr Opin Immunol. 43:60–66. 2016. View Article : Google Scholar : PubMed/NCBI
18	Zhang Y, Qi Y, Zhao Y, Sun H, Ge J and Liu Z: Activin A induces apoptosis of mouse myeloma cells via the mitochondrial pathway. Oncol Lett. 15:2590–2594. 2018.PubMed/NCBI
19	Garcia-Gomez A, Sanchez-Guijo F, Del Cañizo MC, San Miguel JF and Garayoa M: Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics. World J Stem Cells. 6:322–343. 2014. View Article : Google Scholar : PubMed/NCBI
20	Terpos E, Kastritis E, Christoulas D, Gkotzamanidou M, Eleutherakis-Papaiakovou E, Kanellias N, Papatheodorou A and Dimopoulos MA: Circulating activin-A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post-lenalidomide and dexamethasone therapy. Ann Oncol. 23:2681–2686. 2012. View Article : Google Scholar : PubMed/NCBI
21	Cubillos-Ruiz JR, Bettigole SE and Glimcher LH: Tumorigenic and immunosuppressive effects of endoplasmic reticulum stress in cancer. Cell. 168:692–706. 2017. View Article : Google Scholar : PubMed/NCBI
22	Fernández A, Ordóñez R, Reiter RJ, González-Gallego J and Mauriz JL: Melatonin and endoplasmic reticulum stress: Relation to autophagy and apoptosis. J Pineal Res. 59:292–307. 2015. View Article : Google Scholar : PubMed/NCBI
23	Wachmann K, Pop C, van Raam BJ, Drag M, Mace PD, Snipas SJ, Zmasek C, Schwarzenbacher R, Salvesen GS and Riedl SJ: Activation and specificity of human caspase-10. Biochemistry. 49:8307–8315. 2010. View Article : Google Scholar : PubMed/NCBI
24	Su J, Zhou L, Xia MH, Xu Y, Xiang XY and Sun LK: Bcl-2 family proteins are involved in the signal crosstalk between endoplasmic reticulum stress and mitochondrial dysfunction in tumor chemotherapy resistance. BioMed Res Int. 2014:2343702014. View Article : Google Scholar : PubMed/NCBI
25	Yamakawa N, Tsuchida K and Sugino H: The ras GAP-binding protein, Dok-1, mediates activin signaling via serine/threonine kinase receptors. EMBO J. 21:1684–1694. 2002. View Article : Google Scholar : PubMed/NCBI
26	Dong Y, Kalueff AV and Song C: N-methyl-d-aspartate receptor-mediated calcium overload and endoplasmic reticulum stress are involved in interleukin-1beta-induced neuronal apoptosis in rat hippocampus. J Neuroimmunol. 307:7–13. 2017. View Article : Google Scholar : PubMed/NCBI
27	Mc Cullough KD, Martindale JL, Klotz LO, Aw TY and Holbrook NJ: Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol. 21:1249–1259. 2001. View Article : Google Scholar : PubMed/NCBI
28	Huang J, Fairbrother W and Reed JC: Therapeutic targeting of Bcl-2 family for treatment of B-cell malignancies. Expert Rev Hematol. 8:283–297. 2015. View Article : Google Scholar : PubMed/NCBI
29	Sano R and Reed JC: ER stress-induced cell death mechanisms. Biochim Biophys Acta. 1833:3460–3470. 2013. View Article : Google Scholar : PubMed/NCBI
30	Mihailidou C, Papazian I, Papavassiliou AG and Kiaris H: CHOP-dependent regulation of p21/waf1 during ER stress. Cell Physiol Biochem. 25:761–766. 2010. View Article : Google Scholar : PubMed/NCBI
31	Wu YM, Chen ZJ, Jiang GM, Zhang KS, Liu Q, Liang SW, Zhou Y, Huang HB, Du J and Wang HS: Inverse agonist of estrogen-related receptor α suppresses the growth of triple negative breast cancer cells through ROS generation and interaction with multiple cell signaling pathways. Oncotarget. 7:12568–12581. 2016.PubMed/NCBI
32	Kapur A, Felder M, Fass L, Kaur J, Czarnecki A, Rathi K, Zeng S, Osowski KK, Howell C, Xiong MP, et al: Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation. Sci Rep. 6:275302016. View Article : Google Scholar : PubMed/NCBI
33	Duclos C, Lavoie C and Denault JB: Caspases rule the intracellular trafficking cartel. FEBS J. 284:1394–1420. 2017. View Article : Google Scholar : PubMed/NCBI
34	García de la Cadena S and Massieu L: Caspases and their role in inflammation and ischemic neuronal death. Focus on caspase-12. Apoptosis. 21:763–777. 2016. View Article : Google Scholar : PubMed/NCBI
35	Lu XS, Qiao YB, Li Y, Yang B, Chen MB and Xing CG: Preclinical study of cinobufagin as a promising anti-colorectal cancer agent. Oncotarget. 8:988–998. 2017.PubMed/NCBI
36	Nakagawa T and Yuan J: Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J Cell Biol. 150:887–894. 2000. View Article : Google Scholar : PubMed/NCBI
37	Miyazawa K, Shinozaki M, Hara T, Furuya T and Miyazono K: Two major Smad pathways in TGF-beta superfamily signaling. Genes Cells. 7:1191–1204. 2002. View Article : Google Scholar : PubMed/NCBI
38	Liu M, Mao C, Li J, Han F and Yang P: Effects of the activin A-follistatin system on myocardial cell apoptosis through the endoplasmic reticulum stress pathway in heart failure. Int J Mol Sci. 18:E3742017. View Article : Google Scholar : PubMed/NCBI
39	Liu Z, Gu H, Gan L, Xu Y, Feng F, Saeed M and Sun C: Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue. Oncotarget. 8:9267–9279. 2017.PubMed/NCBI