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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells

Authors: Ke Jiang, Yingchun Li, Qiumin Zhu, Jiansheng Xu, Yupeng Wang, Wuguo Deng, Quentin Liu, Guirong Zhang, Songshu Meng

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

Oncolytic viruses represent a promising therapy against cancers with acquired drug resistance. However, low efficacy limits its clinical application. The objective of this study is to investigate whether pharmacologically modulating autophagy could enhance oncolytic Newcastle disease virus (NDV) strain NDV/FMW virotherapy of drug-resistant lung cancer cells.

Methods

The effect of NDV/FMW infection on autophagy machinery in A549 lung cancer cell lines resistant to cisplatin (A549/DDP) or paclitaxel (A549/PTX) was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, formation of double-membrane vesicles and conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). The effects of autophagy inhibitor chloroquine (CQ) and autophagy inducer rapamycin on NDV/FMW-mediated antitumor activity were evaluated both in culture cells and in mice bearing drug-resistant lung cancer cells.

Results

We show that NDV/FMW triggers autophagy in A549/PTX cells via dampening the class I PI3K/Akt/mTOR/p70S6K pathway, which inhibits autophagy. On the contrary, NDV/FMW infection attenuates the autophagic process in A549/DDP cells through the activation of the negative regulatory pathway. Furthermore, combination with CQ or knockdown of ATG5 significantly enhances NDV/FMW-mediated antitumor effects on A549/DDP cells, while the oncolytic efficacy of NDV/FMW in A549/PTX cells is significantly improved by rapamycin. Interestingly, autophagy modulation does not increase virus progeny in these drug resistant cells. Importantly, CQ or rapamycin significantly potentiates NDV/FMW oncolytic activity in mice bearing A549/DDP or A549/PTX cells respectively.

Conclusions

These results demonstrate that combination treatment with autophagy modulators is an effective strategy to augment the therapeutic activity of NDV/FMW against drug-resistant lung cancers.
Appendix
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Literature
1.
Brozovic A, Osmak M: Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance. Cancer Lett. 2007, 251 (1): 1-16.CrossRefPubMed
2.
Hsu DS, Balakumaran BS, Acharya CR, Vlahovic V, Walters KS, Garman K, Anders C, Riedel RF, Lancaster J, Harpole D, Dressman HK, Nevins JR, Febbo PG, Potti A: Pharmacogenomic strategies provide a rational approach to the treatment of cisplatin-resistant patients with advanced cancer. J Clin Oncol. 2007, 25 (28): 4350-4357.CrossRefPubMed
3.
Beljanski V, Hiscott J: The use of oncolytic viruses to overcome lung cancer drug resistance. Curr Opin Virol. 2012, 2 (5): 629-635.CrossRefPubMed
4.
Meng S, Zhou Z, Chen F, Kong X, Liu H, Jiang K, Liu W, Hu M, Zhang X, Ding C, Wu Y: Newcastle disease virus induces apoptosis in cisplatin-resistant human lung adenocarcinoma A549 cells in vitro and in vivo. Cancer Lett. 2012, 317 (1): 56-64.CrossRefPubMed
5.
Reichard KW, Lorence RM, Cascino CJ, Peeples ME, Walter RJ, Fernando MB, Reyes HM, Greager JA: Newcastle disease virus selectively kills human tumor cells. J Surg Res. 1992, 52 (5): 448-453.CrossRefPubMed
6.
Schirrmacher V, Bai L, Umansky V, Yu L, Xing Y, Qian Z: Newcastle disease virus activates macrophages for anti-tumor activity. Int J Oncol. 2000, 16 (2): 363-373.PubMed
7.
Phuangsab A, Lorence RM, Reichard KW, Peeples ME, Walter RJ: Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Lett. 2001, 172 (1): 27-36.CrossRefPubMed
8.
Bian J, Wang K, Kong X, Liu H, Chen F, Hu M, Zhang X, Jiao X, Ge B, Wu Y, Meng S: Caspase- and p38-MAPK-dependent induction of apoptosis in A549 lung cancer cells by Newcastle disease virus. Arch Virol. 2011, 156 (8): 1335-1344.CrossRefPubMed
9.
Wu Y, Zhang X, Wang X, Wang L, Hu S, Liu X, Meng S: Apoptin enhances the oncolytic properties of Newcastle disease virus. Intervirology. 2012, 55 (4): 276-286.CrossRefPubMed
10.
Yaacov B, Eliahoo E, Lazar I, Ben-Shlomo M, Greenbaum I, Panet A, Zakay-Rones Z: Selective oncolytic effect of an attenuated Newcastle disease virus (NDV-HUJ) in lung tumors. Cancer Gene Ther. 2008, 15 (12): 795-807.CrossRefPubMed
11.
Yaacov B, Lazar I, Tayeb S, Frank S, Izhar U, Lotem M, Perlman R, Ben-Yehuda D, Zakay-Rones Z, Panet A: Extracellular matrix constituents interfere with Newcastle disease virus spread in solid tissue and diminish its potential oncolytic activity. J Gen Virol. 2012, 93 (Pt 8): 1664-1672.CrossRefPubMed
12.
Lazar I, Yaacov B, Shiloach T, Eliahoo E, Kadouri L, Lotem M, Perlman R, Zakay-Rones Z, Panet A, Ben-Yehuda D: The oncolytic activity of Newcastle disease virus NDV-HUJ on chemoresistant primary melanoma cells is dependent on the proapoptotic activity of the inhibitor of apoptosis protein Livin. J Virol. 2010, 84 (1): 639-646.CrossRefPubMed
13.
Mansour M, Palese P, Zamarin D: Oncolytic specificity of Newcastle disease virus is mediated by selectivity for apoptosis-resistant cells. J Virol. 2011, 85 (12): 6015-6023.CrossRefPubMedPubMedCentral
14.
Szeberenyi J, Fabian Z, Torocsik B, Kiss K, Csatary LK: Newcastle disease virus-induced apoptosis in PC12 pheochromocytoma cells. Am J Ther. 2003, 10 (4): 282-288.CrossRefPubMed
15.
Elankumaran S, Rockemann D, Samal SK: Newcastle disease virus exerts oncolysis by both intrinsic and extrinsic caspase-dependent pathways of cell death. J Virol. 2006, 80 (15): 7522-7534.CrossRefPubMedPubMedCentral
16.
Fabian Z, Csatary CM, Szeberenyi J, Csatary LK: p53-independent endoplasmic reticulum stress-mediated cytotoxicity of a Newcastle disease virus strain in tumor cell lines. J Virol. 2007, 81 (6): 2817-2830.CrossRefPubMedPubMedCentral
17.
Meng C, Zhou Z, Jiang K, Yu S, Jia L, Wu Y, Liu Y, Meng S, Ding C: Newcastle disease virus triggers autophagy in U251 glioma cells to enhance virus replication. Arch Virol. 2012, 157 (6): 1011-1018.CrossRefPubMed
18.
Xie Z, Klionsky DJ: Autophagosome formation: core machinery and adaptations. Nat Cell Biol. 2007, 9 (10): 1102-1109.CrossRefPubMed
19.
Kraft C, Martens S: Mechanisms and regulation of autophagosome formation. Curr Opin Cell Biol. 2012, 24 (4): 496-501.CrossRefPubMed
20.
21.
22.
Meng S, Xu J, Wu Y, Ding C: Targeting autophagy to enhance oncolytic virus-based cancer therapy. Expert Opin Biol Ther. 2013, 13 (6): 863-873.CrossRefPubMed
23.
Rodriguez-Rocha H, Gomez-Gutierrez JG, Garcia-Garcia A, Rao XM, Chen L, McMasters KM, Zhou HS: Adenoviruses induce autophagy to promote virus replication and oncolysis. Virology. 2011, 416 (1–2): 9-15.CrossRefPubMedPubMedCentral
24.
Jiang H, White EJ, Rios-Vicil CI, Xu J, Gomez-Manzano C, Fueyo J: Human adenovirus type 5 induces cell lysis through autophagy and autophagy-triggered caspase activity. J Virol. 2011, 85 (10): 4720-4729.CrossRefPubMedPubMedCentral
25.
Yokoyama T, Iwado E, Kondo Y, Aoki H, Hayashi Y, Georgescu MM, Sawaya R, Hess KR, Mills GB, Kawamura H, Hashimoto Y, Urata Y, Fujiwara T, Kondo S: Autophagy-inducing agents augment the antitumor effect of telerase-selve oncolytic adenovirus OBP-405 on glioblastoma cells. Gene Ther. 2008, 15 (17): 1233-1239.CrossRefPubMed
26.
Botta G, Passaro C, Libertini S, Abagnale A, Barbato S, Maione AS, Hallden G, Beguinot F, Formisano P, Portella G: Inhibition of autophagy enhances the effects of E1A-defective oncolytic adenovirus dl922-947 against glioma cells in vitro and in vivo. Hum Gene Ther. 2012, 23 (6): 623-634.CrossRefPubMed
27.
Cheng PH, Lian S, Zhao R, Rao XM, McMasters KM, Zhou HS: Combination of autophagy inducer rapamycin and oncolytic adenovirus improves antitumor effect in cancer cells. Virol J. 2013, 10: 293-CrossRefPubMedPubMedCentral
28.
Bartlett DL, Liu Z, Sathaiah M, Ravindranathan R, Guo Z, He Y, Guo ZS: Oncolytic viruses as therapeutic cancer vaccines. Mol Cancer. 2013, 12 (1): 103-CrossRefPubMedPubMedCentral
29.
Guo ZS, Liu Z, Bartlett DL: Oncolytic Immunotherapy: Dying the Right Way is a Key to Eliciting Potent Antitumor Immunity. Front Oncol. 2014, 4: 74-PubMedPubMedCentral
30.
Liikanen I, Ahtiainen L, Hirvinen ML, Bramante S, Cerullo V, Nokisalmi P, Hemminki O, Diaconu I, Pesonen S, Koski A, Kangasniemi L, Pesonen SK, Oksanen M, Laasonen L, Partanen K, Joensuu T, Zhao F, Kanerva A, Hemminki A: Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients. Mol Ther. 2013, 21 (6): 1212-1223.CrossRefPubMedPubMedCentral
31.
Jiang ZK, Johnson M, Moughon DL, Kuo J, Sato M, Wu L: Rapamycin enhances adenovirus-mediated cancer imaging and therapy in pre-immunized murine hosts. PLoS One. 2013, 8 (9): e73650-CrossRefPubMedPubMedCentral
32.
Kim EH, Min HY, Chung HJ, Song J, Park HJ, Kim S, Lee SK: Anti-proliferative activity and suppression of P-glycoprotein by (−)-antofine, a natural phenanthroindolizidine alkaloid, in paclitaxel-resistant human lung cancer cells. Food Chem Toxicol. 2012, 50 (3–4): 1060-1065.CrossRefPubMed
33.
Zou Z, Yuan Z, Zhang Q, Long Z, Chen J, Tang Z, Zhu Y, Chen S, Xu J, Yan M, Wang J, Liu Q: Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells. Autophagy. 2012, 8 (12): 1798-1810.CrossRefPubMedPubMedCentral
34.
Shingu T, Chumbalkar VC, Gwak HS, Fujiwara K, Kondo S, Farrell NP, Bogler O: The polynuclear platinum BBR3610 induces G2/M arrest and autophagy early and apoptosis late in glioma cells. Neuro Oncol. 2010, 12 (12): 1269-1277.PubMedPubMedCentral
35.
Sun Y, Yu S, Ding N, Meng C, Meng S, Zhang S, Zhan Y, Qiu X, Tan L, Chen H, Song C, Ding C: Autophagy benefits the replication of Newcastle disease virus in chicken cells and tissues. J Virol. 2014, 88 (1): 525-537.CrossRefPubMedPubMedCentral
36.
Chen L, Meng S, Wang H, Bali P, Bai W, Li B, Atadja P, Bhalla KN, Wu J: Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. Mol Cancer Ther. 2005, 4 (9): 1311-1319.CrossRefPubMed
37.
Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000, 19 (21): 5720-5728.CrossRefPubMedPubMedCentral
38.
Ren JH, He WS, Nong L, Zhu QY, Hu K, Zhang RG, Huang LL, Zhu F, Wu G: Acquired cisplatin resistance in human lung adenocarcinoma cells is associated with enhanced autophagy. Cancer Biother Radiopharm. 2010, 25 (1): 75-80.CrossRefPubMed
39.
Yue Z, Jin S, Yang C, Levine AJ, Heintz N: Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003, 100 (25): 15077-15082.CrossRefPubMedPubMedCentral
40.
Alonso MM, Jiang H, Yokoyama T, Xu J, Bekele NB, Lang FF, Kondo S, Gomez-Manzano C, Fueyo J: Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. Mol Ther. 2008, 16 (3): 487-493.CrossRefPubMed
41.
Lun XQ, Jang JH, Tang N, Deng H, Head R, Bell JC, Stojdl DF, Nutt CL, Senger DL, Forsyth PA, McCart JA: Efficacy of systemically administered oncolytic vaccinia virotherapy for malignant gliomas is enhanced by combination therapy with rapamycin or cyclophosphamide. Clin Cancer Res. 2009, 15 (8): 2777-2788.CrossRefPubMed
42.
Lun X, Alain T, Zemp FJ, Zhou H, Rahman MM, Hamilton MG, McFadden G, Bell J, Senger DL, Forsyth PA: Myxoma virus virotherapy for glioma in immunocompetent animal models: optimizing administration routes and synergy with rapamycin. Cancer Res. 2010, 70 (2): 598-608.CrossRefPubMed
43.
Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, Metivier D, Meley D, Souquere S, Yoshimori T, Pierron G, Codogno P, Kroemer G: Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 2005, 25 (3): 1025-1040.CrossRefPubMedPubMedCentral
44.
Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, Thomas-Tikhonenko A, Thompson CB: Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest. 2007, 117 (2): 326-336.CrossRefPubMedPubMedCentral
45.
Enzenmuller S, Gonzalez P, Debatin KM, Fulda S: Chloroquine overcomes resistance of lung carcinoma cells to the dual PI3K/mTOR inhibitor PI103 by lysosome-mediated apoptosis. Anticancer Drugs. 2013, 24 (1): 14-19.CrossRefPubMed
46.
Ji C, Zhang L, Cheng Y, Patel R, Wu H, Zhang Y, Wang M, Ji S, Belani CP, Yang JM, Ren X: Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer. Cancer Biol Ther. 2014, 15 (5): 570-577.CrossRefPubMedPubMedCentral
47.
Waqar SN, Gopalan PK, Williams K, Devarakonda S, Govindan R: A phase I trial of sunitinib and rapamycin in patients with advanced non-small cell lung cancer. Chemotherapy. 2013, 59 (1): 8-13.CrossRefPubMed
48.
Chaabane W, User SD, El-Gazzah M, Jaksik R, Sajjadi E, Rzeszowska-Wolny J, Los MJ: Autophagy, apoptosis, mitoptosis and necrosis: interdependence between those pathways and effects on cancer. Arch Immunol Ther Exp (Warsz). 2013, 61 (1): 43-58.CrossRef
49.
Jain MV, Paczulla AM, Klonisch T, Dimgba FN, Rao SB, Roberg K, Schweizer F, Lengerke C, Davoodpour P, Palicharla VR, Maddika S, Los M: Interconnections between apoptotic, autophagic and necrotic pathways: implications for cancer therapy development. J Cell Mol Med. 2013, 17 (1): 12-29.CrossRefPubMedPubMedCentral
50.
Alain T, Lun X, Martineau Y, Sean P, Pulendran B, Petroulakis E, Zemp FJ, Lemay CG, Roy D, Bell JC, Thomas G, Kozma SC, Forsyth PA, Costa-Mattioli M, Sonenberg N: Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production. Proc Natl Acad Sci U S A. 2010, 107 (4): 1576-1581.CrossRefPubMedPubMedCentral
51.
Thomas DL, Doty R, Tosic V, Liu J, Kranz DM, McFadden G, Macneill AL, Roy EJ: Myxoma virus combined with rapamycin treatment enhances adoptive T cell therapy for murine melanoma brain tumors. Cancer Immunol Immunother. 2011, 60 (10): 1461-1472.CrossRefPubMedPubMedCentral
52.
Yu H, Su J, Xu Y, Kang J, Li H, Zhang L, Yi H, Xiang X, Liu F, Sun L: p62/SQSTM1 involved in cisplatin resistance in human ovarian cancer cells by clearing ubiquitinated proteins. Eur J Cancer. 2011, 47 (10): 1585-1594.CrossRefPubMed
53.
Ajabnoor GM, Crook T, Coley HM: Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells. Cell Death Dis. 2012, 3: e260-CrossRefPubMedPubMedCentral
54.
Veldhoen RA, Banman SL, Hemmerling DR, Odsen R, Simmen T, Simmonds AJ, Underhill DA, Goping IS: The chemotherapeutic agent paclitaxel inhibits autophagy through two distinct mechanisms that regulate apoptosis. Oncogene. 2013, 32 (6): 736-746.CrossRefPubMed
55.
Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S, Roz E, Caserini R, Lo Vullo S, Camerini T, Mariani L, Delia D, Calabro E, Pastorino U, Sozzi G: Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci U S A. 2009, 106 (38): 16281-16286.CrossRefPubMedPubMedCentral
56.
Barr MP, Gray SG, Hoffmann AC, Hilger RA, Thomale J, O'Flaherty JD, Fennell DA, Richard D, O'Leary JJ, O'Byrne KJ: Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS One. 2013, 8 (1): e54193-CrossRefPubMedPubMedCentral
Metadata
Title
Pharmacological modulation of autophagy enhances Newcastle disease virus-mediated oncolysis in drug-resistant lung cancer cells
Authors
Ke Jiang
Yingchun Li
Qiumin Zhu
Jiansheng Xu
Yupeng Wang
Wuguo Deng
Quentin Liu
Guirong Zhang
Songshu Meng
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-551

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