Crizotinib induces apoptosis of lung cancer cells through JAK-STAT pathway

Lu,Hongmin; Wu,Shibo; Chen,Huafei; Huang,Ying; Qiu,Guoqin; Liu,Lingxiang; Li,Yong

doi:10.3892/ol.2018.9387

Crizotinib induces apoptosis of lung cancer cells through JAK-STAT pathway

Authors:
- Hongmin Lu
- Shibo Wu
- Huafei Chen
- Ying Huang
- Guoqin Qiu
- Lingxiang Liu
- Yong Li
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Affiliations: Department of Medical Oncology, Renji Hospital Shanghai Jiaotong University School of Medicine, Shanghai 200000, P.R. China, Department of Respiratory Medicine, Li Huili Hospital, Ningbo Medical Center, Ningbo, Zhejiang 315041, P.R. China, Department of Thoracic Surgery, Zhejiang Rongjun Hospital, Jiaxing, Zhejiang 314001, P.R. China, Department of Respiratory Medicine, The First Hospital Affiliated to AMU (Southwest Hospital), Chongqing 400038, P.R. China, Department of Thoracic Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China, Department of Oncology, Jiangsu Province Hospital, Nanjing, Jiangsu 210029, P.R. China, Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
Published online on: September 4, 2018 https://doi.org/10.3892/ol.2018.9387
Pages: 5992-5996
Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Effect of crizotinib on apoptosis of lung cancer cells was investigated. Human non-small cell lung adenocarcinoma H2228 cells were cultured in the presence of 0, 20, 40, 80, 160 and 320 nmol/l of crizotinib for 3 days, respectively. The inhibition rate of cell proliferation was measured by MTT assay, and half maximal inhibitory concentration (IC50) was calculated. Cell apoptosis was detected by flow cytometry. Transwell assay was performed to detect cell migration. Expression of Janus protein tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) proteins was detected by western blot analysis. Crizotinib significantly inhibited the proliferation of human lung cancer H2228 cells, and the inhibitory effect was enhanced with the increase of the concentration of crizotinib (p<0.01). The IC50 value was 311.26 nnol/l. According to IC50 value, concentration of crizotinib at 300 nmol/l was selected for the study. It was found that crizotinib at 300 nmol/l significantly promoted cell apoptosis (p<0.01) and inhibited cell migration (p<0.01). Compared with pretreatment levels, crizotinib downregulated the expression of JAK and STAT (p<0.01) on the 1st day of treatment, but with the prolongation of time, no further significant difference was observed on the 1st, 2nd or 3rd day in the level of JAK protein (p=0.47); there were no statistically significant differences in the level of STAT protein (p=0.91). Crizotinib can inhibit the migration and promote cell apoptosis of human lung cancer cell line H2228 by regulating the expression of JAK and STAT proteins in JAK-STAT signaling pathway.

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1	Watza D, Cote ML and Schwartz AG: Lung Cancer: geneticseLS. John Wiley & Sons, Ltd.; Chichester: 2017, View Article : Google Scholar
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Wakeford R and Tawn EJ: Paternal irradiation and leukemia in offspring. Radiat Res. 154:222–223. 2000. View Article : Google Scholar : PubMed/NCBI
4	Pappa E, Nikitakis N, Vlachodimitropoulos D, Avgoustidis D, Oktseloglou V and Papadogeorgakis N: Phosphorylated signal transducer and activator of transcription-1 immunohistochemical expression is associated with improved survival in patients with oral squamous cell carcinoma. J Oral Maxillofac Surg. 72:211–221. 2014. View Article : Google Scholar : PubMed/NCBI
5	Leeman RJ, Lui VW and Grandis JR: STAT3 as a therapeutic target in head and neck cancer. Expert Opin Biol Ther. 6:231–241. 2006. View Article : Google Scholar : PubMed/NCBI
6	Proietti C, Salatino M, Rosemblit C, Carnevale R, Pecci A, Kornblihtt AR, Molinolo AA, Frahm I, Charreau EH, Schillaci R, et al: Progestins induce transcriptional activation of signal transducer and activator of transcription 3 (Stat3) via a Jak- and Src-dependent mechanism in breast cancer cells. Mol Cell Biol. 25:4826–4840. 2005. View Article : Google Scholar : PubMed/NCBI
7	Gonçalves J and Silva AP: Methamphetamine and the JAK/STAT pathwayNeuropathology of Drug Addictions and Substance Misuse. Preedy VR: 2. 1st edition. Academic Press; Cambridge, MA: pp. 147–154. 2016, View Article : Google Scholar
8	Schütz A, Röser K, Klitzsch J, Lieder F, Aberger F, Gruber W, Mueller KM, Pupyshev A, Moriggl R and Friedrich K: Lung adenocarcinomas and lung cancer cell lines show association of MMP-1 expression with STAT3 activation. Trans Oncol. 8:97–105. 2015. View Article : Google Scholar
9	de la Bellacasa Puig R, Karachaliou N, Estrada-Tejedor R, Teixidó J, Costa C and Borrell JI: ALK and ROS1 as a joint target for the treatment of lung cancer: A review. Transl Lung Cancer Res. 2:72–86. 2013.PubMed/NCBI
10	Xu W, Kim JW, Jung WJ, Koh Y and Yoon SS: Crizotinib in combination with everolimus synergistically inhibits proliferation of ALK-positive anaplastic large cell lymphoma. Cancer Res Treat. Jun 19–2017.(Epub ahead of print). https://doi.org/10.4143/crt.2016.357
11	Adlakha YK and Saini N: MicroRNA: A connecting road between apoptosis and cholesterol metabolism. Tumour Biol. 37:8529–8554. 2016. View Article : Google Scholar : PubMed/NCBI
12	Han Y, Park S, Kinyua AW, Andera L, Kim KW and Kim I: Emetine enhances the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of pancreatic cancer cells by downregulation of myeloid cell leukemia sequence-1 protein. Oncol Rep. 31:456–462. 2014. View Article : Google Scholar : PubMed/NCBI
13	Ahn HK, Jeon K, Yoo H, Han B, Lee SJ, Park H, Lee MJ, Ha SY, Han JH, Sun JM, et al: Successful treatment with crizotinib in mechanically ventilated patients with ALK positive non-small-cell lung cancer. J Thorac Oncol. 8:250–253. 2013. View Article : Google Scholar : PubMed/NCBI
14	Roth W: Cell death in malignant tumors. Relevance of cell death regulation for metastasis. Pathologe. 36 Suppl 2:181–184. 2015.(In German). View Article : Google Scholar : PubMed/NCBI
15	Song X, Zhang Z, Wang S, Li H, Zuo H, Xu X, Weng S, He J and Li C: A Janus Kinase in the JAK/STAT signaling pathway from Litopenaeus vannamei is involved in antiviral immune response. Fish Shellfish Immunol. 44:662–673. 2015. View Article : Google Scholar : PubMed/NCBI
16	Lee TS, Kantarjian H, Ma W, Yeh CH, Giles F and Albitar M: Effects of clinically relevant MPL mutations in the transmembrane domain revealed at the atomic level through computational modeling. PLoS One. 6:e233962011. View Article : Google Scholar : PubMed/NCBI
17	Rozovski U, Wu JY, Harris DM, Liu Z, Li P, Hazan-Halevy I, Ferrajoli A, Burger JA, O'Brien S, Jain N, et al: Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells. Blood. 123:3797–3802. 2014. View Article : Google Scholar : PubMed/NCBI
18	Jiang J, Liu Y, Tang Y, Li L, Zeng R, Zeng S and Zhong M: ALDH1A1 induces resistance to CHOP in diffuse large B-cell lymphoma through activation of the JAK2/STAT3 pathway. Onco Targets Ther. 9:5349–5360. 2016. View Article : Google Scholar : PubMed/NCBI
19	Jiang R, Wang X, Jin Z and Li K: Association of nuclear PIM1 expression with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma and squamous cell carcinoma. J Cancer. 7:324–334. 2016. View Article : Google Scholar : PubMed/NCBI
20	Chu Q, Shen D, He L, Wang H, Liu C and Zhang W: Prognostic significance of SOCS3 and its biological function in colorectal cancer. Gene. 627:114–122. 2017. View Article : Google Scholar : PubMed/NCBI
21	Xue F, Zhu L, Meng QW, Wang L, Chen XS, Zhao YB, Xing Y, Wang XY and Cai L: FAT10 is associated with the malignancy and drug resistance of non-small-cell lung cancer. Onco Targets Ther. 9:4397–4409. 2016. View Article : Google Scholar : PubMed/NCBI