Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells

Authors: Xiaomin Feng, Hao Liu, Zhijie Zhang, Yixue Gu, Huisi Qiu, Zhimin He

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

Login to get access

Abstract

Background

Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. We previously identified that Annexin A2 is significantly up-regulated in cisplatin-resistant non-small cell lung cancer (NSCLC) A549/DDP cells. However, the exact function and molecular mechanism of Annexin A2 in cisplatin resistance of NSCLCs has not been determined.

Methods

Western blot and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. Immunohistochemistry was performed to analyze the expression of Annexin A2 in NSCLC tissue samples. MTS assay, Colony formation assays, AnnexinV/PI apoptosis assay, Luciferase Reporter Assay, Chromatin-immunoprecipitation, and nude mice xenograft assay were used to visualize the function of Annexin A2 on cisplatin resistance.

Results

Our results demonstrated that knockdown of Annexin A2 increased cisplatin sensitivity of cisplatin-resistant A549/DDP cells both in vitro and in vivo, whereas overexpression of Annexin A2 increased cisplatin resistance of A549, H460 and H1650 cells. Moreover, we found that Annexin A2 enhanced cisplatin resistance via inhibition of cisplatin-induced cell apoptosis. Our studies showed that Annexin A2 suppressed the expression of p53 through activation of JNK/c-Jun signaling, which in turn resulted in a decrease in the expression of p53-regulated apoptotic genes p21, GADD45 and BAX, as well as p53-dependent cell apoptosis. Furthermore, we found that in NSCLC cases that Annexin A2 is highly expressed; it is positively correlated with a poor prognosis, as well as correlated with short disease-free survival for patients who received chemotherapy after surgery.

Conclusions

These data suggested that Annexin A2 induces cisplatin resistance of NSCLCs via regulation of JNK/c-Jun/p53 signaling, and provided an evidence that blockade of Annexin A2 could serve as a novel therapeutic approach for overcoming drug resistance in NSCLCs.
Appendix
Available only for authorised users
Literature
1.
2.
Siegel R, DeSantis C, Virgo K, Stein K, Mariotto A, Smith T, Cooper D, Gansler T, Lerro C, Fedewa S, Lin C, Leach C, Cannady RS, Cho H, Scoppa S, Hachey M, Kirch R, Jemal A, Ward E. Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin. 2012;62(4):220–41.CrossRefPubMed
3.
Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med. 2004;350(4):351–60.CrossRefPubMed
4.
Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92–8.CrossRefPubMed
5.
6.
Lokman NA, Ween MP, Oehler MK, Ricciardelli C. The role of annexin A2 in tumorigenesis and cancer progression. Cancer Microenviron. 2011;4(2):199–208.CrossRefPubMedPubMedCentral
7.
Reeves SA, Chavez-Kappel C, Davis R, Rosenblum M, Israel MA. Developmental regulation of annexin II (Lipocortin 2) in human brain and expression in high grade glioma. Cancer Res. 1992;52(24):6871–6.PubMed
8.
Duncan R, Carpenter B, Main LC, Telfer C, Murray GI. Characterisation and protein expression profiling of annexins in colorectal cancer. Br J Cancer. 2008;98(2):426–33.CrossRefPubMed
9.
Emoto K, Sawada H, Yamada Y, Fujimoto H, Takahama Y, Ueno M, Takayama T, Uchida H, Kamada K, Naito A, Hirao S, Nakajima Y. Annexin II overexpression is correlated with poor prognosis in human gastric carcinoma. Anticancer Res. 2001;21(2B):1339–45.PubMed
10.
Vishwanatha JK, Chiang Y, Kumble KD, Hollingsworth MA, Pour PM. Enhanced expression of annexin II in human pancreatic carcinoma cells and primary pancreatic cancers. Carcinogenesis. 1993;14(12):2575–9.CrossRefPubMed
11.
Chuthapisith S, Bean BE, Cowley G, Eremin JM, Samphao S, Layfield R, Kerr ID, Wiseman J, El-Sheemy M, Sreenivasan T, Eremin O. Annexins in human breast cancer: possible predictors of pathological response to neoadjuvant chemotherapy. Eur J Cancer. 2009;45(7):1274–81.CrossRefPubMed
12.
Mohammad HS, Kurokohchi K, Yoneyama H, Tokuda M, Morishita A, Jian G, Shi L, Murota M, Tani J, Kato K, Miyoshi H, Deguchi A, Himoto T, Usuki H, Wakabayashi H, Izuishi K, Suzuki Y, Iwama H, Deguchi K, Uchida N, Sabet EA, Arafa UA, Hassan AT, El-Sayed AA, Masaki T. Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma. Int J Oncol. 2008;33(6):1157–63.PubMed
13.
Wang CY, Chen CL, Tseng YL, Fang YT, Lin YS, Su WC, Chen CC, Chang KC, Wang YC, Lin CF. Annexin A2 silencing induces G2 arrest of non-small cell lung cancer cells through p53-dependent and -independent mechanisms. J Biol Chem. 2012;287(39):32512–24.CrossRefPubMedPubMedCentral
14.
Wang CY, Lin CF. Annexin A2: its molecular regulation and cellular expression in cancer development. Dis Markers. 2014;2014:308976.PubMedPubMedCentral
15.
Deng L, Gao Y, Li X, Cai M, Wang H, Zhuang H, Tan M, Liu S, Hao Y, Lin B. Expression and clinical significance of annexin A2 and human epididymis protein 4 in endometrial carcinoma. J Exp Clin Cancer Res. 2015;34:96.CrossRefPubMedPubMedCentral
16.
Chuthapisith S, Layfield R, Kerr ID, Hughes C, Eremin O. Proteomic profiling of MCF-7 breast cancer cells with chemoresistance to different types of anti-cancer drugs. Int J Oncol. 2007;30(6):1545–51.PubMed
17.
Zhang F, Zhang L, Zhang B, Wei X, Yang Y, Qi RZ, Ying G, Zhang N, Niu R. Anxa2 Plays a critical role in enhanced invasiveness of the multidrug resistant human breast cancer cells. J Proteome Res. 2009;8(11):5041–7.CrossRefPubMed
18.
Kagawa S, Takano S, Yoshitomi H, Kimura F, Satoh M, Shimizu H, Yoshidome H, Ohtsuka M, Kato A, Furukawa K, Matsushita K, Nomura F, Miyazaki M. Akt/mTOR signaling pathway is crucial for gemcitabine resistance induced by Annexin II in pancreatic cancer cells. J Surg Res. 2012;178(2):758–67.CrossRefPubMed
19.
Jung H, Kim JS, Kim WK, Oh KJ, Kim JM, Lee HJ, Han BS, Kim DS, Seo YS, Lee SC, Park SG, Bae KH. Intracellular annexin A2 regulates NF-kappaB signaling by binding to the p50 subunit: implications for gemcitabine resistance in pancreatic cancer. Cell Death Dis. 2015;6:e1606.CrossRefPubMedPubMedCentral
20.
Liu H, Gu YX, Yin J, Zheng GP, Wang CK, Zhang ZJ, Deng M, Liu JF, Jia XT, He ZM. SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell. Cell Signal. 2014;26(12):2710–20.CrossRefPubMed
21.
Gyorffy B, Surowiak P, Budczies J, Lanczky A. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One. 2013;8(12):e82241.CrossRefPubMedPubMedCentral
22.
Xie K, Liang C, Li Q, Yan C, Wang C, Gu Y, Zhu M, Du F, Wang H, Dai J, Liu X, Jin G, Shen H, Ma H, Hu Z. Role of ATG10 expression quantitative trait loci in non-small cell lung cancer survival. Int J Cancer. 2016;139(7):1564–73.CrossRefPubMed
23.
Wilson TR, Johnston PG, Longley DB. Anti-apoptotic mechanisms of drug resistance in cancer. Curr Cancer Drug Targets. 2009;9(3):307–19.CrossRefPubMed
24.
Rusch V, Klimstra D, Venkatraman E, Oliver J, Martini N, Gralla R, Kris M, Dmitrovsky E. Aberrant p53 expression predicts clinical resistance to cisplatin-based chemotherapy in locally advanced non-small cell lung cancer. Cancer Res. 1995;55(21):5038–42.PubMed
25.
Zhang ZD, Li Y, Fan LQ, Zhao Q, Tan BB, Zhao XF. Annexin A2 is implicated in multi-drug-resistance in gastric cancer through p38MAPK and AKT pathway. Neoplasma. 2014;61(6):627–37.CrossRefPubMed
26.
Das M, Jiang F, Sluss HK, Zhang C, Shokat KM, Flavell RA, Davis RJ. Suppression of p53-dependent senescence by the JNK signal transduction pathway. Proc Natl Acad Sci U S A. 2007;104(40):15759–64.CrossRefPubMedPubMedCentral
27.
Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, Wagner EF. Liver tumor development. C-Jun antagonizes the proapoptotic activity of p53. Cell. 2003;112(2):181–92.CrossRefPubMed
28.
Ginsberg D, Oren M, Yaniv M, Piette J. Protein-binding elements in the promoter region of the mouse p53 gene. Oncogene. 1990;5(9):1285–90.PubMed
29.
Stepniak E, Ricci R, Eferl R, Sumara G, Sumara I, Rath M, Hui L, Wagner EF. C-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Genes Dev. 2006;20(16):2306–14.CrossRefPubMedPubMedCentral
30.
Schreiber M, Kolbus A, Piu F, Szabowski A, Mohle-Steinlein U, Tian JM, Karin M, Angel P, Wagner EF. Control of cell cycle progression by c-Jun is p53 dependent. Genes Dev. 1999;13(5):607–19.CrossRefPubMedPubMedCentral
31.
Seve P, Dumontet C. Chemoresistance in non-small cell lung cancer. Curr Med Chem Anticancer Agents. 2005;5(1):73–88.CrossRefPubMed
32.
Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer. 2013;13(10):714–26.CrossRefPubMed
33.
Hall MD, Okabe M, Shen DW, Liang XJ, Gottesman MM. The role of cellular accumulation in determining sensitivity to platinum-based chemotherapy. Annu Rev Pharmacol Toxicol. 2008;48:495–535.CrossRefPubMed
34.
Ferreira JA, Peixoto A, Neves M, Gaiteiro C, Reis CA, Assaraf YG, Santos LL. Mechanisms of cisplatin resistance and targeting of cancer stem cells: adding glycosylation to the equation. Drug Resist Updat. 2016;24:34–54.CrossRefPubMed
35.
Chen J, Wang L, Tang Y, Gong G, Liu L, Chen M, Chen Z, Cui Y, Li C, Cheng X, Qi L, Zu X. Maspin enhances cisplatin chemosensitivity in bladder cancer T24 and 5637 cells and correlates with prognosis of muscle-invasive bladder cancer patients receiving cisplatin based neoadjuvant chemotherapy. J Exp Clin Cancer Res. 2016;35:2.CrossRefPubMedPubMedCentral
36.
Letai AG. Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer. 2008;8(2):121–32.CrossRefPubMed
37.
38.
Wang CY, Lin YS, Su WC, Chen CL, Lin CF. Glycogen synthase kinase-3 and Omi/HtrA2 induce annexin A2 cleavage followed by cell cycle inhibition and apoptosis. Mol Biol Cell. 2009;20(19):4153–61.CrossRefPubMedPubMedCentral
39.
Waters KM, Stenoien DL, Sowa MB, von Neubeck C, Chrisler WB, Tan R, Sontag RL, Weber TJ. Annexin A2 modulates radiation-sensitive transcriptional programming and cell fate. Radiat Res. 2013;179(1):53–61.CrossRefPubMed
40.
Vazquez A, Bond EE, Levine AJ, Bond GL. The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov. 2008;7(12):979–87.CrossRefPubMed
41.
Lowe SW, Ruley HE, Jacks T, Housman DE. p53-Dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell. 1993;74(6):957–67.CrossRefPubMed
42.
Gregorc V, Ludovini V, Pistola L, Darwish S, Floriani I, Bellezza G, Sidoni A, Cavaliere A, Scheibel M, De Angelis V, Bucciarelli E, Tonato M. Relevance of p53, bcl-2 and Rb expression on resistance to cisplatin-based chemotherapy in advanced non-small cell lung cancer. Lung Cancer. 2003;39(1):41–8.CrossRefPubMed
43.
Li M, Li S, Liu B, Gu MM, Zou S, Xiao BB, Yu L, Ding WQ, Zhou PK, Zhou J, Shang ZF. PIG3 Promotes NSCLC cell mitotic progression and is associated with poor prognosis of NSCLC patients. J Exp Clin Cancer Res. 2017;36(1):39.CrossRefPubMedPubMedCentral
44.
Huang Y, Yan CH, Fu SB. The cloning and expression of apoptosis associated gene ANNEXIN A2 induced by p53 gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2005;22(6):661–4.PubMed
45.
Madureira PA, Hill R, Lee PW, Waisman DM. Genotoxic agents promote the nuclear accumulation of annexin A2: role of annexin A2 in mitigating DNA damage. PLoS One. 2012;7(11):e50591.CrossRefPubMedPubMedCentral
46.
Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9(8):537–49.CrossRefPubMed
47.
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–90.CrossRefPubMed
48.
Madureira PA, Hill R, Miller VA, Giacomantonio C, Lee PWK, Waisman DM. Annexin A2 is a novel cellular redox regulatory protein involved in tumorigenesis. Oncotarget. 2011;2(12):1075–93.CrossRefPubMedPubMedCentral
49.
Leppa S, Bohmann D. Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene. 1999;18(45):6158–62.CrossRefPubMed
50.
Hayakawa J, Depatie C, Ohmichi M, Mercola D. The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair. J Biol Chem. 2003;278(23):20582–92.CrossRefPubMed
51.
Lo Iacono M, Monica V, Vavala T, Gisabella M, Saviozzi S, Bracco E, Novello S, Papotti M, Scagliotti GV. ATF2 Contributes to cisplatin resistance in non-small cell lung cancer and celastrol induces cisplatin resensitization through inhibition of JNK/ATF2 pathway. Int J Cancer. 2015;136(11):2598–609.CrossRefPubMed
52.
Sui X, Kong N, Wang X, Fang Y, Hu X, Xu Y, Chen W, Wang K, Li D, Jin W, Lou F, Zheng Y, Hu H, Gong L, Zhou X, Pan H, Han W. JNK confers 5-fluorouracil resistance in p53-deficient and mutant p53-expressing colon cancer cells by inducing survival autophagy. Sci Rep. 2014;4:4694.CrossRefPubMedPubMedCentral
53.
Khatlani TS, Wislez M, Sun M, Srinivas H, Iwanaga K, Ma L, Hanna AE, Liu D, Girard L, Kim YH, Pollack JR, Minna JD, Wistuba II, Kurie JM. C-Jun N-terminal kinase is activated in non-small-cell lung cancer and promotes neoplastic transformation in human bronchial epithelial cells. Oncogene. 2007;26(18):2658–66.CrossRefPubMed
54.
Antonyak MA, Moscatello DK, Wong AJ. Constitutive activation of c-Jun N-terminal kinase by a mutant epidermal growth factor receptor. J Biol Chem. 1998;273(5):2817–22.CrossRefPubMed
55.
Li JY, Wang H, May S, Song X, Fueyo J, Fuller GN. Constitutive activation of c-Jun N-terminal kinase correlates with histologic grade and EGFR expression in diffuse gliomas. J Neuro-Oncol. 2008;88(1):11–7.CrossRef
56.
Chaudhary P, Thamake SI, Shetty P, Vishwanatha JK. Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies. Br J Cancer. 2014;111(12):2328–41.CrossRefPubMedPubMedCentral
Metadata
Title
Annexin A2 contributes to cisplatin resistance by activation of JNK-p53 pathway in non-small cell lung cancer cells
Authors
Xiaomin Feng
Hao Liu
Zhijie Zhang
Yixue Gu
Huisi Qiu
Zhimin He
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0594-1

Other articles of this Issue 1/2017

Journal of Experimental & Clinical Cancer Research 1/2017 Go to the issue

Research

Combined targeting of Arf1 and Ras potentiates anticancer activity for prostate cancer therapeutics

Erratum

Erratum to: Elaboration of a nomogram to predict nonsentinel node status in breast cancer patients with positive sentinel node, intraoperatively assessed with one step nucleic amplification: Retrospective and validation phase

Research

Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter

Research

Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2

Research

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Research

Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits