Upregulation of phosphatase and tensin homolog is essential for the effect of 4-aminopyridine on A549/CDDP cells

Luo,Zhengyi; Wang,Jiafeng; Li,Chenglin; Qiu,Yumiao; Huang,Jing; Huang,Yujie; Gu,Hongli; Wu,Bin; Hu,Zhe; Zhen,Yan

doi:10.3892/mmr.2018.8585

Upregulation of phosphatase and tensin homolog is essential for the effect of 4-aminopyridine on A549/CDDP cells

Authors:
- Zhengyi Luo
- Jiafeng Wang
- Chenglin Li
- Yumiao Qiu
- Jing Huang
- Yujie Huang
- Hongli Gu
- Bin Wu
- Zhe Hu
- Yan Zhen
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Affiliations: Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
Published online on: February 8, 2018 https://doi.org/10.3892/mmr.2018.8585
Pages: 5996-6001

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Abstract

4-aminopyridine (4-AP), a voltage-gated potassium channel blocker, was revealed to possess pro‑apoptotic properties in various types of cancer cells. The present study aimed to explore the effect of 4‑AP on a cisplatin (DDP) resistant lung cancer cell line A549/CDDP and the underlying mechanism by which it had an effect. In the present study, an MTT assay and cell cycle analysis were used to determine that 4‑AP inhibited cell growth in vitro and a tumorigenesis assay in nude mice determined that 4‑AP also inhibited cell growth in vivo. 4‑AP induced cell apoptosis of A549/CDDP cells observed by electron microscopy and Annexin V‑APC/7‑ADD analysis. In addition, 4‑AP enhanced the sensitivity of A549/CDDP cells to DDP as revealed by an MTT assay. Mechanistically, 4‑AP upregulated the phosphatase and tensin homolog (PTEN) and modulated the phosphoinositide 3‑kinase/protein kinase B signaling pathway and its downstream cell cycle factors, including cyclin D1, cyclin‑dependent kinase 4 and p21, as well as apoptosis‑associated proteins B‑cell lymphoma 2, pro‑caspase 9, pro‑caspase 3, cleaved caspase 9 and cleaved caspase 3. The effects of 4‑AP on cell growth and apoptosis were reversed by PTEN silencing. In conclusion, the results indicated that 4‑AP inhibited cell growth, induced apoptosis and sensitized A549/CDDP cells to DDP via the upregulation of PTEN. 4‑AP may be a potential therapeutic agent for patients with DDP resistance.

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1	Califano R, Karamouzis MV, Banerjee S, de Azambuja E, Guarneri V, Hutka M, Jordan K, Kamposioras K, Martinelli E, Corral J, et al: Use of adjuvant chemotherapy (CT) and radiotherapy (RT) in incompletely resected (R1) early stage non-small cell lung cancer (NSCLC): A European survey conducted by the European society for medical oncology (ESMO) young oncologists committee. Lung Cancer. 85:74–80. 2014. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
3	Stewart DJ: Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol. 63:12–31. 2007. View Article : Google Scholar : PubMed/NCBI
4	Chin LS, Park CC, Zitnay KM, Sinha M, DiPatri AJ Jr, Perillán P and Simard JM: 4-Aminopyridine causes apoptosis and blocks an outward rectifier K+ channel in malignant astrocytoma cell lines. J Neurosci Res. 48:122–127. 1997. View Article : Google Scholar : PubMed/NCBI
5	Kim JA, Kang YS, Jung MW, Kang GH, Lee SH and Lee YS: Ca2+ influx mediates apoptosis induced by 4-aminopyridine, a K+ channel blocker, in HepG2 human hepatoblastoma cells. Pharmacology. 60:74–81. 2000. View Article : Google Scholar : PubMed/NCBI
6	Wang W, Xiao J, Adachi M, Liu Z and Zhou J: 4-aminopyridine induces apoptosis of human acute myeloid leukemia cells via increasing [Ca2+]i through P2X7 receptor pathway. Cell Physiol Biochem. 28:199–208. 2011. View Article : Google Scholar : PubMed/NCBI
7	Huang L, Li B, Li W, Guo H and Zou F: ATP-sensitive potassium channels control glioma cells proliferation by regulating ERK activity. Carcinogenesis. 30:737–744. 2009. View Article : Google Scholar : PubMed/NCBI
8	Dai T, Zhou Q, Zeng X, He J, Yang Y, Li C, Ren D, Liu L and Liao B: A study on the characteristics of the membrane potassium channels in human non-small cell lung cancer cell. Zhongguo Fei Ai Za Zhi. 4:281–286. 2001.(In Chinese). PubMed/NCBI
9	Zhen Y, Liu Z, Yang H, Yu X, Wu Q, Hua S, Long X, Jiang Q, Song Y, Cheng C, et al: Tumor suppressor PDCD4 modulates miR-184-mediated direct suppression of C-MYC and BCL2 blocking cell growth and survival in nasopharyngeal carcinoma. Cell Death Dis. 4:e8722013. View Article : Google Scholar : PubMed/NCBI
10	Ru Q, Tian X, Wu YX, Wu RH, Pi MS and Li CY: Voltage-gated and ATP-sensitive K+ channels are associated with cell proliferation and tumorigenesis of human glioma. Oncol Rep. 31:842–848. 2014. View Article : Google Scholar : PubMed/NCBI
11	Wang H, Wu Q, Liu Z, Luo X, Fan Y, Liu Y, Zhang Y, Hua S, Fu Q, Zhao M, et al: Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma. Cell Death Dis. 5:e11552014. View Article : Google Scholar : PubMed/NCBI
12	Huang L, Wang HY, Li JD, Wang JH, Zhou Y, Luo RZ, Yun JP, Zhang Y, Jia WH and Zheng M: KPNA2 promotes cell proliferation and tumorigenicity in epithelial ovarian carcinoma through upregulation of c-Myc and downregulation of FOXO3a. Cell Death Dis. 4:e7452013. View Article : Google Scholar : PubMed/NCBI
13	Jiang W, Kahn SM, Zhou P, Zhang YJ, Cacace AM, Infante AS, Doi S, Santella RM and Weinstein IB: Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene. 8:3447–3457. 1993.PubMed/NCBI
14	Baldin V, Lukas J, Marcote MJ, Pagano M and Draetta G: Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7:812–821. 1993. View Article : Google Scholar : PubMed/NCBI
15	Kroemer G, El-Deiry WS, Golstein P, Peter ME, Vaux D, Vandenabeele P, Zhivotovsky B, Blagosklonny MV, Malorni W, Knight RA, et al: Classification of cell death: Recommendations of the nomenclature committee on cell death. Cell Death Differ. 12 Suppl 2:S1463–S1467. 2005. View Article : Google Scholar
16	Galluzzi L, Maiuri MC, Vitale I, Zischka H, Castedo M, Zitvogel L and Kroemer G: Cell death modalities: Classification and pathophysiological implications. Cell Death Differ. 14:1237–1243. 2007. View Article : Google Scholar : PubMed/NCBI
17	Cory S and Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
18	Shi Y: Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell. 9:459–470. 2002. View Article : Google Scholar : PubMed/NCBI
19	Dong-Dong L, Xi-Ran Z and Xiang-Rong C: Expression and significance of new tumor suppressor gene PTEN in primary liver cancer. J Cell Mol Med. 7:67–71. 2003. View Article : Google Scholar : PubMed/NCBI
20	Luo H, Yang Y, Duan J, Wu P, Jiang Q and Xu C: PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis. 4:e4812013. View Article : Google Scholar : PubMed/NCBI
21	Florea AM and Büsselberg D: Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers (Basel). 3:1351–1371. 2011. View Article : Google Scholar : PubMed/NCBI