Activin A induces apoptosis of human lung adenocarcinoma A549 cells through endoplasmic reticulum stress pathway

Zhang,Fenglin; Qi,Yan; Li,Jing; Liu,Boyang; Liu,Zhonghui; Cui,Xueling

doi:10.3892/or.2023.8688

Activin A induces apoptosis of human lung adenocarcinoma A549 cells through endoplasmic reticulum stress pathway

Authors:
- Fenglin Zhang
- Yan Qi
- Jing Li
- Boyang Liu
- Zhonghui Liu
- Xueling Cui
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Affiliations: 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, Key Laboratory of Neuroimmunology and Clinical Immunology in Jilin, Changchun, Jilin 130021, P.R. China
Published online on: December 20, 2023 https://doi.org/10.3892/or.2023.8688
Article Number: 29
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Activin A, a member of the transforming growth factor‑β (TGF‑β) superfamily, has been implicated in the tumorigenesis and progression of various cancers. However, it remains unclear whether activin A induces apoptosis in human lung adenocarcinoma cells through the endoplasmic reticulum (ER) stress pathway. In the present study, BrdU, flow cytometry and western blotting were used to examine cell proliferation, apoptosis and protein expression, respectively. The present study revealed that activin A inhibited human lung adenocarcinoma A549 cell proliferation, induced apoptosis, and upregulated the protein levels of C/EBP homologous protein (CHOP), growth arrest and DNA damage‑inducible protein 34 (GADD34), cleaved‑caspase‑3 and caspase‑12. Furthermore, the administration of activin A did not alter the levels of suppressor of mothers against decapentaplegic 3 (Smad3) or phosphorylated (p)‑Smad3 proteins, whereas, it significantly elevated the levels of ActRIIA and p‑extracellular signal regulated kinase proteins 1 and 2 (ERK1/2) proteins in A549 cells. The apoptotic effects of activin A on A549 cells were attenuated by the ERK inhibitor FR180204, which also downregulated CHOP and caspase‑12 protein levels. Additionally, activin A increased intracellular calcium flux in A549 cells, and the calcium ion chelator BAPTA acetoxymethyl ester (BAPTA‑AM) inhibited activin A‑induced A549 cell apoptosis, whereas the calcium agonist ionomycin significantly increased apoptosis of A549 cells induced by activin A. These findings indicated that the activation of the ER stress pathway resulting in apoptosis of A549 cells triggered by activin A is facilitated by the ActRIIA‑ERK1/2 signaling and calcium signaling. The present findings suggest that the agonists of ERK and calcium signaling exhibit promising clinical therapeutic potential for the induction of apoptosis in lung adenocarcinoma.

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1	Siegel RL, Miller KD, Wagle NS and Jemal A: Cancer statistics, 2023. CA Cancer J Clin. 73:17–48. 2023. View Article : Google Scholar : PubMed/NCBI
2	Herbst RS, Morgensztern D and Boshoff C: The biology and management of non-small cell lung cancer. Nature. 553:446–454. 2018. View Article : Google Scholar : PubMed/NCBI
3	Yu Z, Tang H, Chen S, Xie Y, Shi L, Xia S, Jiang M, Li J and Chen D: Exosomal LOC85009 inhibits docetaxel resistance in lung adenocarcinoma through regulating ATG5-induced autophagy. Drug Resist Updat. 67:1009152023. View Article : Google Scholar : PubMed/NCBI
4	Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, Kramer J and Siegel RL: Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 72:409–436. 2022. View Article : Google Scholar : PubMed/NCBI
5	Zhao C, Zhai Y, Geng R, Wu K, Song W, Ai N and Ge W: Genetic analysis of activin/inhibin beta subunits in zebrafish development and reproduction. PLoS Genet. 18:e10105232022. View Article : Google Scholar : PubMed/NCBI
6	Ge J, Sun H, Li J, Shan Y, Zhao Y, Liao F, Yang Y, Cui X and Liu Z: Involvement of CHOP in activin A-induced myeloma NS-1 cell apoptosis. Oncol Rep. 42:2644–2654. 2019.PubMed/NCBI
7	Seder CW, Hartojo W, Lin L, Silvers AL, Wang Z, Thomas DG, Giordano TJ, Chen G, Chang AC, Orringer MB and Beer DG: Upregulated INHBA expression may promote cell proliferation and is associated with poor survival in lung adenocarcinoma. Neoplasia. 11:388–396. 2009. View Article : Google Scholar : PubMed/NCBI
8	Yu SY, Luan Y, Tang S, Abazarikia A, Dong R, Caffrey TC, Hollingsworth MA, Oupicky D and Kim SY: Uncovering tumor-promoting roles of activin a in pancreatic ductal adenocarcinoma. Adv Sci (Weinh). 10:e22070102023. View Article : Google Scholar : PubMed/NCBI
9	Kalli M, Mpekris F, Wong CK, Panagi M, Ozturk S, Thiagalingam S, Stylianopoulos T and Papageorgis P: Activin a signaling regulates IL13Rα2 expression to promote breast cancer metastasis. Front Oncol. 9:322019. View Article : Google Scholar : PubMed/NCBI
10	Ervolino De Oliveira C, Dourado MR, Sawazaki-Calone Í, Costa De Medeiros M, Rossa Júnior C, De Karla Cervigne N, Esquiche León J, Lambert D, Salo T, Graner E and Coletta RD: Activin A triggers angiogenesis via regulation of VEGFA and its overexpression is associated with poor prognosis of oral squamous cell carcinoma. Int J Oncol. 57:364–376. 2020. View Article : Google Scholar : PubMed/NCBI
11	Oakes SA and Papa FR: The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol. 10:173–194. 2015. View Article : Google Scholar : PubMed/NCBI
12	Di Conza G and Ho PC: ER stress responses: An emerging modulator for innate immunity. Cells. 9:6952020. View Article : Google Scholar : PubMed/NCBI
13	Fu X, Cui J, Meng X, Jiang P, Zheng Q, Zhao W and Chen X: Endoplasmic reticulum stress, cell death and tumor: Association between endoplasmic reticulum stress and the apoptosis pathway in tumors (Review). Oncol Rep. 45:801–808. 2021. View Article : Google Scholar : PubMed/NCBI
14	Xue LX, Liu HY, Cui Y, Dong Y, Wang JQ, Ji QY, He JT, Yao M, Wang YY, Shao YK, et al: Neuroprotective effects of Activin A on endoplasmic reticulum stress-mediated apoptotic and autophagic PC12 cell death. Neural Regen Res. 12:779–786. 2017. View Article : Google Scholar : PubMed/NCBI
15	Jiang L, Qi Y, Kong X, Wang R, Qi J, Lin F, Cui X and Liu Z: Activin A as a novel chemokine induces migration of L929 fibroblasts by ERK signaling in microfluidic devices. Front Cell Dev Biol. 9:6603162021. View Article : Google Scholar : PubMed/NCBI
16	Jiang L, Liu B, Qi Y, Zhu L, Cui X and Liu Z: Antagonistic effects of activin A and TNF-alpha on the activation of L929 fibroblast cells via Smad3-independent signaling. Sci Rep. 10:206232020. View Article : Google Scholar : PubMed/NCBI
17	Li J, Qi Y, Yang K, Zhu L, Cui X and Liu Z: Follistatin is a novel chemoattractant for migration and invasion of placental trophoblasts of mice. Cells. 11:38162022. View Article : Google Scholar : PubMed/NCBI
18	Norgard RJ, Pitarresi JR, Maddipati R, Aiello-Couzo NM, Balli D, Li J, Yamazoe T, Wengyn MD, Millstein ID, Folkert IW, et al: Calcium signaling induces a partial EMT. EMBO Rep. 22:e518722021. View Article : Google Scholar : PubMed/NCBI
19	Patergnani S, Danese A, Bouhamida E, Aguiari G, Previati M, Pinton P and Giorgi C: Various aspects of calcium signaling in the regulation of apoptosis, autophagy, cell proliferation, and cancer. Int J Mol Sci. 21:83232020. View Article : Google Scholar : PubMed/NCBI
20	Moon DO: Calcium's role in orchestrating cancer apoptosis: Mitochondrial-centric perspective. Int J Mol Sci. 24:89822023. View Article : Google Scholar : PubMed/NCBI
21	Valero-Aracama MJ, Zheng F and Alzheimer C: Dorsal-Ventral gradient of activin regulates strength of GABAergic inhibition along longitudinal axis of mouse hippocampus in an Activity-Dependent fashion. Int J Mol Sci. 24:131452023. View Article : Google Scholar : PubMed/NCBI
22	Bloise E, Ciarmela P, Dela Cruz C, Luisi S, Petraglia F and Reis FM: Activin a in mammalian physiology. Physiol Rev. 99:739–780. 2019. View Article : Google Scholar : PubMed/NCBI
23	Hashimoto O, Funaba M, Sekiyama K, Doi S, Shindo D, Satoh R, Itoi H, Oiwa H, Morita M, Suzuki C, et al: Activin e controls energy homeostasis in both brown and white adipose tissues as a hepatokine. Cell Rep. 25:1193–1203. 2018. View Article : Google Scholar : PubMed/NCBI
24	Liu G, Qi Y, Wu J, Lin F, Liu Z and Cui X: Follistatin is a crucial chemoattractant for mouse decidualized endometrial stromal cell migration by JNK signalling. J Cell Mol Med. 27:127–140. 2023. View Article : Google Scholar : PubMed/NCBI
25	Locci M, Wu JE, Arumemi F, Mikulski Z, Dahlberg C, Miller AT and Crotty S: Activin A programs the differentiation of human TFH cells. Nat Immunol. 17:976–984. 2016. View Article : Google Scholar : PubMed/NCBI
26	Ge J, Fan Y, Lu Y, Qi Y, Wang M and Liu Z: Activin A increases arterial pressure in the hypothalamic paraventricular nucleus in rats by angiotension II. Neuroreport. 27:683–688. 2016. View Article : Google Scholar : PubMed/NCBI
27	Dzierlega K, Chakraborty M, Lee M, Soliman AM, Parker D, Khan S, Chan YT, Akbari M, Yokota T, Winer S, et al: Activin A-Expressing polymorphonuclear Myeloid-Derived suppressor cells infiltrate skeletal and cardiac muscle and promote cancer cachexia. J Immunol. 211:497–507. 2023. View Article : Google Scholar : PubMed/NCBI
28	Staudacher JJ, Arnold A, Kühl AA, Pötzsch M, Daum S, Winterfeld M, Berg E, Hummel M, Rau B, Stein U and Treese C: Prognostic impact of activin subunit inhibin beta A in gastric and esophageal adenocarcinomas. BMC Cancer. 22:9532022. View Article : Google Scholar : PubMed/NCBI
29	Hamang M, Yaden B and Dai G: Gastrointestinal pharmacology activins in liver health and disease. Biochem Pharmacol. 214:1156682023. View Article : Google Scholar : PubMed/NCBI
30	Meier D, Lodberg A, Gvozdenovic A, Pellegrini G, Neklyudova O, Born W, Fuchs B, Eijken M and M Botter S: Inhibition of the activin receptor signaling pathway: A novel intervention against osteosarcoma. Cancer Med. 10:286–296. 2021. View Article : Google Scholar : PubMed/NCBI
31	Tao JJ, Cangemi NA, Makker V, Cadoo KA, Liu JF, Rasco DW, Navarro WH, Haqq CM and Hyman DM: First-in-human phase I study of the activin A inhibitor, STM 434, in patients with granulosa cell ovarian cancer and other advanced solid tumors. Clin Cancer Res. 25:5458–5465. 2019. View Article : Google Scholar : PubMed/NCBI
32	Cheng X and Ferrell JE Jr: Apoptosis propagates through the cytoplasm as trigger waves. Science. 361:607–612. 2018. View Article : Google Scholar : PubMed/NCBI
33	Zhang P, Ruan Y, Xiao J, Chen F and Zhang X: Association of serum follistatin levels with histological types and progression of tumor in human lung cancer. Cancer Cell Int. 18:1622018. View Article : Google Scholar : PubMed/NCBI
34	Chen F, Ren P, Feng Y, Liu H, Sun Y, Liu Z, Ge J and Cui X: Follistatin is a novel biomarker for lung adenocarcinoma in humans. PLoS One. 9:e1113982014. View Article : Google Scholar : PubMed/NCBI
35	Pistritto G, Trisciuoglio D, Ceci C, Garufi A and D'Orazi G: Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging (Albany NY). 8:603–619. 2016. View Article : Google Scholar : PubMed/NCBI
36	Liu S, Luo L, Zuo F, Geng Y, Ou Y, Chen D, Yang S, Luo W, Wang Y, Wang J and Huang X: Immunosuppression and apoptosis activation mediated by p53-Bcl2/Bax signaling pathway-The potential mechanism of goldfish (Carassius auratus Linnaeus) gill disease caused by Myxobolus ampullicapsulatus. Front Immunol. 13:9989752022. View Article : Google Scholar : PubMed/NCBI
37	Geng Y, Liu P, Xie Y, Liu Y, Zhang X, Hou X and Zhang L: Xanthatin suppresses pancreatic cancer cell growth via the ROS/RBL1 signaling pathway: In vitro and in vivo insights. Phytomedicine. 119:1550042023. View Article : Google Scholar : PubMed/NCBI
38	Marini KD, Croucher DR, McCloy RA, Vaghjiani V, Gonzalez-Rajal A, Hastings JF, Chin V, Szczepny A, Kostyrko K, Marquez C, et al: Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy. Sci Transl Med. 10:eaat35042018. View Article : Google Scholar : PubMed/NCBI
39	Yuan C, Ni L and Wu X: Activin A activation drives renal fibrosis through the STAT3 signaling pathway. Int J Biochem Cell Biol. 134:1059502021. View Article : Google Scholar : PubMed/NCBI
40	Hotchkiss RS, Strasser A, McDunn JE and Swanson PE: Cell death. N Engl J Med. 361:1570–1583. 2009. View Article : Google Scholar : PubMed/NCBI
41	Kim C and Kim B: Anti-Cancer natural products and their bioactive compounds inducing ER Stress-Mediated apoptosis: A review. Nutrients. 10:10212018. View Article : Google Scholar : PubMed/NCBI
42	Roberts JZ, Crawford N and Longley DB: The role of ubiquitination in apoptosis and necroptosis. Cell Death Differ. 29:272–284. 2022. View Article : Google Scholar : PubMed/NCBI
43	Wong HY, Hui Q, Hao Z, Warnock GL, Woo M, Luciani DS and Marzban L: The role of mitochondrial apoptotic pathway in islet amyloid-induced β-cell death. Mol Cell Endocrinol. 537:1114242021. View Article : Google Scholar : PubMed/NCBI
44	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
45	Green DR: The mitochondrial pathway of apoptosis Part II: The BCL-2 protein family. Cold Spring Harb Perspect Biol. 14:a0410462022. View Article : Google Scholar : PubMed/NCBI
46	Hu H, Tian M, Ding C and Yu S: The C/EBP Homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol. 9:30832018. View Article : Google Scholar : PubMed/NCBI
47	Wang B, Feng Y, Song X, Liu Q, Ning Y, Ou X, Yang J, Zhang X and Wen F: Involvement of ERK, Bcl-2 family and caspase 3 in recombinant human activin A-induced apoptosis in A549. Toxicology. 258:176–183. 2009. View Article : Google Scholar : PubMed/NCBI
48	Wiley MB, Bauer J, Mehrotra K, Zessner-Spitzenberg J, Kolics Z, Cheng W, Castellanos K, Nash MG, Gui X, Kone L, et al: Non-Canonical activin A signaling stimulates Context-dependent and Cellular-Specific outcomes in CRC to promote tumor cell migration and immune tolerance. Cancers (Basel). 15:30032023. View Article : Google Scholar : PubMed/NCBI
49	Sugatani T: Systemic activation of activin a signaling causes chronic kidney Disease-Mineral bone disorder. Int J Mol Sci. 19:24902018. View Article : Google Scholar : PubMed/NCBI
50	Zhang X, Liu T, Huang J and He J: PICALM exerts a role in promoting CRC progression through ERK/MAPK signaling pathway. Cancer Cell Int. 22:1782022. View Article : Google Scholar : PubMed/NCBI
51	Lucas RM, Luo L and Stow JL: ERK1/2 in immune signalling. Biochem Soc Trans. 50:1341–1352. 2022. View Article : Google Scholar : PubMed/NCBI
52	Lu Z and Xu S: ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life. 58:621–631. 2006. View Article : Google Scholar : PubMed/NCBI
53	Zhang J, Zhang J, Liu W, Ge R, Gao T, Tian Q, Mu X, Zhao L and Li X: UBTF facilitates melanoma progression via modulating MEK1/2-ERK1/2 signalling pathways by promoting GIT1 transcription. Cancer Cell Int. 21:5432021. View Article : Google Scholar : PubMed/NCBI
54	Leung GP, Feng T, Sigoillot FD, Geyer FC, Shirley MD, Ruddy DA, Rakiec DP, Freeman AK, Engelman JA, Jaskelioff M and Stuart DD: Hyperactivation of MAPK signaling is deleterious to RAS/RAF-mutant melanoma. Mol Cancer Res. 17:199–211. 2019. View Article : Google Scholar : PubMed/NCBI
55	Lee CY, Hsiao YH, Chen PN, Wu HH, Lu CY, Yang SF and Wang PH: CLEFMA induces intrinsic and extrinsic apoptotic pathways through ERK1/2 and p38 signalling in uterine cervical cancer cells. J Cell Mol Med. 27:446–455. 2023. View Article : Google Scholar : PubMed/NCBI
56	Sugiura R, Satoh R and Takasaki T: ERK: A Double-Edged sword in cancer. ERK-Dependent apoptosis as a potential therapeutic strategy for cancer. Cells. 10:25092021. View Article : Google Scholar : PubMed/NCBI