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Inflammation Research

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01-09-2019 | Lung Cancer | Original Research Paper

Inhibition of JAK2/STAT3 signaling pathway protects mice from the DDP-induced acute kidney injury in lung cancer

Authors: Lei Zhang, Peng Lu, Xu Guo, Ting Liu, Xu Luo, Yi-Tang Zhu

Published in: Inflammation Research | Issue 9/2019

Abstract

Objective

To explore AG490 (the inhibitor of Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway) in cisplatin (DDP)-induced acute kidney injury (AKI) in mice with lung cancer.

Methods

Mice were randomly divided into normal, model, AG490, DDP and DDP + AG490 groups. The lung cancer models were established except for Normal group. The levels of blood urea nitrogen (BUN) and creatinine and the status of oxidative stress were detected. Then, histological changes were assessed by HE and PAS staining and apoptosis by TUNEL experiment. The molecule expressions were detected by qRT-PCR and western blot, and immunohistochemistry, respectively.

Results

DDP inhibited the tumor growth in mice with lung cancer, which was further promoted by the combination with AG490. Mice in the DDP group had elevated levels of BUN and creatinine than those in the Normal group with the increased inflammatory cytokines (TNF-α, IL-6, MCP-1 and CXCL-1) and malondialdehyde (MDA) level and the decreased glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). In addition, DDP could activate the JAK2/STAT3 pathway to promote the apoptosis by upregulating Bax, cleaved caspase-9 and cleaved caspase-3 while downregulating the Bcl-2 in the kidney tissues. DDP + AG490 group showed the alleviated AKI and the improvements in oxidative stress, inflammatory responses and apoptosis in the kidney tissues, as compared to DDP group.

Conclusion

AG490 alleviated DDP-induced AKI in lung cancer mice with improved oxidative stress and inflammation, and the suppression of JAK2/STAT3 pathway.

Chen YM. Update of epidermal growth factor receptor-tyrosine kinase inhibitors in non-small-cell lung cancer. J Chin Med Assoc. 2013;76:249–57.CrossRefPubMed

Bareschino MA, Schettino C, Rossi A, Maione P, Sacco PC, Zeppa R, et al. Treatment of advanced non small cell lung cancer. J Thorac Dis. 2011;3:122–33.PubMedPubMedCentral

Kates M, Perez X, Gribetz J, Swanson SJ, McGinn T, Wisnivesky JP. Validation of a model to predict perioperative mortality from lung cancer resection in the elderly. Am J Respir Crit Care Med. 2009;179:390–5.CrossRefPubMed

Yiu KC, Juergens RA, Swaminath A. Multidisciplinary influence on care of lung cancer patients at the time of diagnosis: a patient survey. Clin Oncol (R Coll Radiol). 2016;28:667.CrossRef

Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:213–22.CrossRefPubMed

Suntharalingam K, Mendoza O, Duarte AA, Mann DJ, Vilar R. A platinum complex that binds non-covalently to DNA and induces cell death via a different mechanism than cisplatin. Metallomics. 2013;5:514–23.CrossRefPubMed

Barabas K, Milner R, Lurie D, Adin C. Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol. 2008;6:1–18.CrossRefPubMed

Soni H, Matthews AT, Pallikkuth S, Gangaraju R, Adebiyi A. gamma-secretase inhibitor DAPT mitigates cisplatin-induced acute kidney injury by suppressing Notch1 signaling. J Cell Mol Med. 2019;23:260–70.CrossRefPubMed

Zhou J, Fan Y, Zhong J, Huang Z, Huang T, Lin S, et al. TAK1 mediates excessive autophagy via p38 and ERK in cisplatin-induced acute kidney injury. J Cell Mol Med. 2018;22:2908–21.CrossRefPubMedPubMedCentral

10.

Zundler S, Neurath MF. Integrating immunologic signaling networks: the JAK/STAT pathway in colitis and colitis-associated cancer. Vaccines (Basel). 2016;4:1–20.CrossRef

11.

Mullen M, Gonzalez-Perez RR. Leptin-induced JAK/STAT signaling and cancer growth. Vaccines (Basel). 2016;4:1–17.CrossRef

12.

Qing Y, Stark GR. Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J Biol Chem. 2004;279:41679–85.CrossRefPubMed

13.

Li R, Rezk A, Miyazaki Y, Hilgenberg E, Touil H, Shen P, et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015;7:310ra166.CrossRefPubMed

14.

Qin JZ, Zhang CL, Kamarashev J, Dummer R, Burg G, Dobbeling U. Interleukin-7 and interleukin-15 regulate the expression of the bcl-2 and c-myb genes in cutaneous T-cell lymphoma cells. Blood. 2001;98:2778–83.CrossRefPubMed

15.

Sarkar M, Khare V, Ghosh MK. The DEAD box protein p68: a novel coactivator of Stat3 in mediating oncogenesis. Oncogene. 2017;36:3080–93.CrossRefPubMed

16.

Levy DE, Inghirami G. STAT3: a multifaceted oncogene. Proc Natl Acad Sci USA. 2006;103:10151–2.CrossRefPubMed

17.

Li H, Lu Y, Pang Y, Li M, Cheng X, Chen J. Propofol enhances the cisplatin-induced apoptosis on cervical cancer cells via EGFR/JAK2/STAT3 pathway. Biomed Pharmacother. 2017;86:324–33.CrossRefPubMed

18.

Hu X, Ma J, Vikash V, Li J, Wu D, Liu Y, et al. Thymoquinone augments cisplatin-induced apoptosis on esophageal carcinoma through mitigating the activation of JAK2/STAT3 pathway. Dig Dis Sci. 2018;63:126–34.CrossRefPubMed

19.

Wang M, Lin T, Wang Y, Gao S, Yang Z, Hong X, et al. CXCL12 suppresses cisplatin-induced apoptosis through activation of JAK2/STAT3 signaling in human non-small-cell lung cancer cells. OncoTargets Ther. 2017;10:3215–24.CrossRef

20.

Zhu S, Zhang C, Weng Q, Ye B. Curcumin protects against acute renal injury by suppressing JAK2/STAT3 pathway in severe acute pancreatitis in rats. Exp Ther Med. 2017;14:1669–74.CrossRefPubMedPubMedCentral

21.

Yang N, Luo M, Li R, Huang Y, Zhang R, Wu Q, et al. Blockage of JAK/STAT signalling attenuates renal ischaemia-reperfusion injury in rat. Nephrol Dial Transplant. 2008;23:91–100.CrossRefPubMed

22.

Orlans FB. Ethical decision making about animal experiments. Ethics Behav. 1997;7:163–71.CrossRefPubMed

23.

Hu R, Ma S, Ke X, Jiang H, Wei D, Wang W. Effect of interleukin-2 treatment combined with magnetic fluid hyperthermia on Lewis lung cancer-bearing mice. Biomed Rep. 2016;4:59–62.CrossRefPubMed

24.

Johansson LH, Borg LA. A spectrophotometric method for determination of catalase activity in small tissue samples. Anal Biochem. 1988;174:331–6.CrossRefPubMed

25.

Zheng H, Liu JF. Studies on the relationship between P13K/AKT signal pathway-mediated MMP-9 gene and lung cancer. Eur Rev Med Pharmacol Sci. 2017;21:753–9.PubMed

26.

Song SG, Yu HY, Ma YW, Zhang F, Xu XY. Inhibition on Numb/Notch signal pathway enhances radiosensitivity of lung cancer cell line H358. Tumour Biol. 2016;37:13705–19.CrossRefPubMed

27.

Zhang ZR, Gao MX, Yang K. Cucurbitacin B inhibits cell proliferation and induces apoptosis in human osteosarcoma cells via modulation of the JAK2/STAT3 and MAPK pathways. Exp Ther Med. 2017;14:805–12.CrossRefPubMedPubMedCentral

28.

Byun HJ, Darvin P, Kang DY, Sp N, Joung YH, Park JH, et al. Silibinin downregulates MMP2 expression via Jak2/STAT3 pathway and inhibits the migration and invasive potential in MDA-MB-231 cells. Oncol Rep. 2017;37:3270–8.CrossRefPubMed

29.

Zhou K, Chen J, Wu J, Wu Q, Jia C, Xu YXZ, et al. Atractylenolide III ameliorates cerebral ischemic injury and neuroinflammation associated with inhibiting JAK2/STAT3/Drp1-dependent mitochondrial fission in microglia. Phytomedicine. 2019;59:152922.CrossRefPubMed

30.

Zhao XB, Qin Y, Niu YL, Yang J. Matrine inhibits hypoxia/reoxygenation-induced apoptosis of cardiac microvascular endothelial cells in rats via the JAK2/STAT3 signaling pathway. Biomed Pharmacother. 2018;106:117–24.CrossRefPubMed

31.

Liu RY, Zeng Y, Lei Z, Wang L, Yang H, Liu Z, et al. JAK/STAT3 signaling is required for TGF-beta-induced epithelial-mesenchymal transition in lung cancer cells. Int J Oncol. 2014;44:1643–51.CrossRefPubMed

32.

Kamran MZ, Patil P, Shirsath K, Gude RP. Tyrosine kinase inhibitor AG490 inhibits the proliferation and migration and disrupts actin organization of cancer cells. J Environ Pathol Toxicol Oncol. 2013;32:361–71.CrossRefPubMed

33.

Ogata Y, Osaki T, Naka T, Iwahori K, Furukawa M, Nagatomo I, et al. Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation. Neoplasia. 2006;8:817–25.CrossRefPubMedPubMedCentral

34.

Zahedi K, Barone S, Destefano-Shields C, Brooks M, Murray-Stewart T, Dunworth M, et al. Activation of endoplasmic reticulum stress response by enhanced polyamine catabolism is important in the mediation of cisplatin-induced acute kidney injury. PLoS One. 2017;12:e0184570.CrossRefPubMedPubMedCentral

35.

Veceric-Haler Z, Cerar A, Perse M. (Mesenchymal) Stem cell-based therapy in cisplatin-induced acute kidney injury animal model: risk of immunogenicity and tumorigenicity. Stem Cells Int. 2017;2017:7304643.CrossRefPubMedPubMedCentral

36.

Wang Z, Li YF, Han XY, Sun YS, Zhang LX, Liu W, et al. Kidney protection effect of ginsenoside Re and its underlying mechanisms on cisplatin-induced kidney injury. Cell Physiol Biochem. 2018;48:2219–29.CrossRefPubMed

37.

Yan W, Xu Y, Yuan Y, Tian L, Wang Q, Xie Y, et al. Renoprotective mechanisms of Astragaloside IV in cisplatin-induced acute kidney injury. Free Radic Res. 2017;51:669–83.PubMed

38.

Palipoch S, Punsawad C. Biochemical and histological study of rat liver and kidney injury induced by cisplatin. J Toxicol Pathol. 2013;26:293–9.CrossRefPubMedPubMedCentral

39.

Ryoo IG, Shin DH, Kang KS, Kwak MK. Involvement of Nrf2-GSH signaling in TGFbeta1-stimulated epithelial-to-mesenchymal transition changes in rat renal tubular cells. Arch Pharm Res. 2015;38:272–81.CrossRefPubMed

40.

Seifi B, Kadkhodaee M, Delavari F, Mikaeili S, Shams S, Ostad SN. Pretreatment with pentoxifylline and N-acetylcysteine in liver ischemia reperfusion-induced renal injury. Ren Fail. 2012;34:610–5.CrossRefPubMed

41.

Son D, Kojima I, Inagi R, Matsumoto M, Fujita T, Nangaku M. Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis. Am J Physiol Ren Physiol. 2008;294:F62–72.CrossRef

42.

Duan W, Yang Y, Yi W, Yan J, Liang Z, Wang N, et al. New role of JAK2/STAT3 signaling in endothelial cell oxidative stress injury and protective effect of melatonin. PLoS One. 2013;8:e57941.CrossRefPubMedPubMedCentral

43.

Gorina R, Sanfeliu C, Galito A, Messeguer A, Planas AM. Exposure of glia to pro-oxidant agents revealed selective Stat1 activation by H₂O₂ and Jak2-independent antioxidant features of the Jak2 inhibitor AG490. Glia. 2007;55:1313–24.CrossRefPubMed

44.

Arany I, Megyesi JK, Nelkin BD, Safirstein RL. STAT3 attenuates EGFR-mediated ERK activation and cell survival during oxidant stress in mouse proximal tubular cells. Kidney Int. 2006;70:669–74.CrossRefPubMed

45.

Neria F, Castilla MA, Sanchez RF, Gonzalez Pacheco FR, Deudero JJ, Calabia O, et al. Inhibition of JAK2 protects renal endothelial and epithelial cells from oxidative stress and cyclosporin A toxicity. Kidney Int. 2009;75:227–34.CrossRefPubMed

46.

Malik S, Bhatia J, Suchal K, Gamad N, Dinda AK, Gupta YK, et al. Nobiletin ameliorates cisplatin-induced acute kidney injury due to its anti-oxidant, anti-inflammatory and anti-apoptotic effects. Exp Toxicol Pathol. 2015;67:427–33.CrossRefPubMed

47.

Sun M, Bu W, Li Y, Zhu J, Zhao J, Zhang P, et al. Danzhi Jiangtang Capsule ameliorates kidney injury via inhibition of the JAK-STAT signaling pathway and increased antioxidant capacity in STZ-induced diabetic nephropathy rats. Biosci Trends. 2019;12:595–604.CrossRefPubMed

48.

Si YN, Bao HG, Xu L, Wang XL, Shen Y, Wang JS, et al. Dexmedetomidine protects against ischemia/reperfusion injury in rat kidney. Eur Rev Med Pharmacol Sci. 2014;18:1843–51.PubMed

49.

Park MS, De Leon M, Devarajan P. Cisplatin induces apoptosis in LLC-PK1 cells via activation of mitochondrial pathways. J Am Soc Nephrol. 2002;13:858–65.CrossRefPubMed

50.

Jiang M, Wang CY, Huang S, Yang T, Dong Z. Cisplatin-induced apoptosis in p53-deficient renal cells via the intrinsic mitochondrial pathway. Am J Physiol Ren Physiol. 2009;296:F983–93.CrossRef

51.

Lv J, Wang X, Liu SY, Liang PF, Feng M, Zhang LL, et al. Protective effect of Fenofibrate in renal ischemia reperfusion injury: involved in suppressing kinase 2 (JAK2)/transcription 3 (STAT3)/p53 signaling activation. Pathol Biol. 2015;63:236–42.CrossRefPubMed

52.

He P, Zhang D, Li H, Yang X, Li D, Zhai Y, et al. Hepatitis B virus X protein modulates apoptosis in human renal proximal tubular epithelial cells by activating the JAK2/STAT3 signaling pathway. Int J Mol Med. 2013;31:1017–29.CrossRefPubMedPubMedCentral

Title: Inhibition of JAK2/STAT3 signaling pathway protects mice from the DDP-induced acute kidney injury in lung cancer
Authors: Lei Zhang
Peng Lu
Xu Guo
Ting Liu
Xu Luo
Yi-Tang Zhu
Publication date: 01-09-2019
Publisher: Springer International Publishing
Keywords: Lung Cancer
Acute Kidney Injury
Lung Cancer
Lung Cancer
Acute Kidney Injury
Published in: Inflammation Research / Issue 9/2019
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-019-01258-4

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Inhibition of JAK2/STAT3 signaling pathway protects mice from the DDP-induced acute kidney injury in lung cancer

Abstract

Objective

Methods

Results

Conclusion

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Abstract

Objective

Methods

Results

Conclusion

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