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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling

Authors: Jiangbo Liu, Jiguang Ma, Zheng Wu, Wei Li, Dong Zhang, Liang Han, Fengfei Wang, Katie M Reindl, Erxi Wu, Qingyong Ma

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

Pancreatic cancer is a leading cause of cancer-related deaths in the world with a 5-year survival rate of less than 6%. Currently, there is no successful therapeutic strategy for advanced pancreatic cancer, and new effective strategies are urgently needed. Recently, an arginine deprivation agent, arginine deiminase, was found to inhibit the growth of some tumor cells (i.e., hepatocellular carcinoma, melanoma, and lung cancer) deficient in argininosuccinate synthetase (ASS), an enzyme used to synthesize arginine. The purpose of this study was to evaluate the therapeutic efficacy of arginine deiminase in combination with gemcitabine, the first line chemotherapeutic drug for patients with pancreatic cancer, and to identify the mechanisms associated with its anticancer effects.

Methods

In this study, we first analyzed the expression levels of ASS in pancreatic cancer cell lines and tumor tissues using immunohistochemistry and RT-PCR. We further tested the effects of the combination regimen of arginine deiminase with gemcitabine on pancreatic cancer cell lines in vitro and in vivo.

Results

Clinical investigation showed that pancreatic cancers with reduced ASS expression were associated with higher survivin expression and more lymph node metastasis and local invasion. Treatment of ASS-deficient PANC-1 cells with arginine deiminase decreased their proliferation in a dose- and time-dependent manner. Furthermore, arginine deiminase potentiated the antitumor effects of gemcitabine on PANC-1 cells via multiple mechanisms including induction of cell cycle arrest in the S phase, upregulation of the expression of caspase-3 and 9, and inhibition of activation of the NF-κB survival pathway by blocking NF-κB p65 signaling via suppressing the nuclear translocation and phosphorylation (serine 536) of NF-κB p65 in vitro. Moreover, arginine deiminase can enhance antitumor activity of gemcitabine-based chemotherapy in the mouse xenograft model.

Conclusions

Our results suggest that arginine deprivation by arginine deiminase, in combination with gemcitabine, may offer a novel effective treatment strategy for patients with pancreatic cancer and potentially improve the outcome of patients with pancreatic cancer.
Appendix
Available only for authorised users
Literature
1.
2.
Siegel R, Ma J, Zou Z, Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 2014, 64 (1): 9-29. 10.3322/caac.21208.CrossRefPubMed
3.
Raimondi S, Maisonneuve P, Lowenfels AB: Epidemiology of pancreatic cancer: an overview. Nat Rev Gastroenterol Hepatol. 2009, 6 (12): 699-708. 10.1038/nrgastro.2009.177.CrossRefPubMed
4.
Cascinu S, Berardi R, Labianca R, Siena S, Falcone A, Aitini E, Barni S, Di Costanzo F, Dapretto E, Tonini G, Pierantoni C, Artale S, Rota S, Floriani I, Scartozzi M, Zaniboni A: Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol. 2008, 9 (1): 39-44. 10.1016/S1470-2045(07)70383-2.CrossRefPubMed
5.
Nakai Y, Isayama H, Sasaki T, Sasahira N, Tsujino T, Toda N, Kogure H, Matsubara S, Ito Y, Togawa O, Arizumi T, Hirano K, Tada M, Omata M, Koike K: A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. Br J Cancer. 2012, 106 (12): 1934-1939. 10.1038/bjc.2012.183.CrossRefPubMedPubMedCentral
6.
Tuinmann G, Hegewisch-Becker S, Zschaber R, Kehr A, Schulz J, Hossfeld DK: Gemcitabine and mitomycin C in advanced pancreatic cancer: a single-institution experience. Anticancer Drugs. 2004, 15 (6): 575-579. 10.1097/01.cad.0000131683.29260.d1.CrossRefPubMed
7.
Barbul A: Arginine: biochemistry, physiology, and therapeutic implications. JPEN J Parenter Enteral Nutr. 1986, 10 (2): 227-238. 10.1177/0148607186010002227.CrossRefPubMed
8.
Ensor CM, Holtsberg FW, Bomalaski JS, Clark MA: Pegylated arginine deiminase (ADI-SS PEG20,000 mw) inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Cancer Res. 2002, 62 (19): 5443-5450.PubMed
9.
Kelly MP, Jungbluth AA, Wu BW, Bomalaski J, Old LJ, Ritter G: Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase. Br J Cancer. 2012, 106 (2): 324-332. 10.1038/bjc.2011.524.CrossRefPubMed
10.
Yoon CY, Shim YJ, Kim EH, Lee JH, Won NH, Kim JH, Park IS, Yoon DK, Min BH: Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. Int J Cancer. 2007, 120 (4): 897-905. 10.1002/ijc.22322.CrossRefPubMed
11.
Kim RH, Coates JM, Bowles TL, McNerney GP, Sutcliffe J, Jung JU, Gandour-Edwards R, Chuang FY, Bold RJ, Kung HJ: Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res. 2009, 69 (2): 700-708. 10.1158/0008-5472.CAN-08-3157.CrossRefPubMedPubMedCentral
12.
Takaku H, Takase M, Abe S, Hayashi H, Miyazaki K: In vivo anti-tumor activity of arginine deiminase purified from Mycoplasma arginini. Int J Cancer. 1992, 51 (2): 244-249. 10.1002/ijc.2910510213.CrossRefPubMed
13.
Feun LG, Marini A, Walker G, Elgart G, Moffat F, Rodgers SE, Wu CJ, You M, Wangpaichitr M, Kuo MT, Sisson W, Jungbluth AA, Bomalaski J, Savaraj N: Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase. Br J Cancer. 2012, 106 (9): 1481-1485. 10.1038/bjc.2012.106.CrossRefPubMedPubMedCentral
14.
Shen LJ, Beloussow K, Shen WC: Modulation of arginine metabolic pathways as the potential anti-tumor mechanism of recombinant arginine deiminase. Cancer Lett. 2006, 231 (1): 30-35. 10.1016/j.canlet.2005.01.007.CrossRefPubMed
15.
Bowles TL, Kim R, Galante J, Parsons CM, Virudachalam S, Kung HJ, Bold RJ: Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase. Int J Cancer. 2008, 123 (8): 1950-1955. 10.1002/ijc.23723.CrossRefPubMedPubMedCentral
16.
Burris HR, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997, 15 (6): 2403-2413.PubMed
17.
Mukherjee S, Hurt CN, Bridgewater J, Falk S, Cummins S, Wasan H, Crosby T, Jephcott C, Roy R, Radhakrishna G, McDonald A, Ray R, Joseph G, Staffurth J, Abrams RA, Griffiths G, Maughan T: Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 2013, 14 (4): 317-326. 10.1016/S1470-2045(13)70021-4.CrossRefPubMedPubMedCentral
18.
Karnitz LM, Flatten KS, Wagner JM, Loegering D, Hackbarth JS, Arlander SJ, Vroman BT, Thomas MB, Baek YU, Hopkins KM, Lieberman HB, Chen J, Cliby WA, Kaufmann SH: Gemcitabine-induced activation of checkpoint signaling pathways that affect tumor cell survival. Mol Pharmacol. 2005, 68 (6): 1636-1644.PubMed
19.
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): 758-767. 10.1016/j.jss.2012.05.065.CrossRefPubMed
20.
Shrikhande SV, Kleeff J, Kayed H, Keleg S, Reiser C, Giese T, Buchler MW, Esposito I, Friess H: Silencing of X-linked inhibitor of apoptosis (XIAP) decreases gemcitabine resistance of pancreatic cancer cells. Anticancer Res. 2006, 26 (5A): 3265-3273.PubMed
21.
Singh S, Srivastava SK, Bhardwaj A, Owen LB, Singh AP: CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy. Br J Cancer. 2010, 103 (11): 1671-1679. 10.1038/sj.bjc.6605968.CrossRefPubMedPubMedCentral
22.
Bafna S, Kaur S, Momi N, Batra SK: Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin. Br J Cancer. 2009, 101 (7): 1155-1161. 10.1038/sj.bjc.6605285.CrossRefPubMedPubMedCentral
23.
Arlt A, Gehrz A, Muerkoster S, Vorndamm J, Kruse ML, Folsch UR, Schafer H: Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene. 2003, 22 (21): 3243-3251. 10.1038/sj.onc.1206390.CrossRefPubMed
24.
Zheng C, Jiao X, Jiang Y, Sun S: ERK1/2 activity contributes to gemcitabine resistance in pancreatic cancer cells. J Int Med Res. 2013, 41 (2): 300-306. 10.1177/0300060512474128.CrossRefPubMed
25.
Sizemore N, Leung S, Stark GR: Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol. 1999, 19 (7): 4798-4805.CrossRefPubMedPubMedCentral
26.
Madrid LV, Mayo MW, Reuther JY, Baldwin AJ: Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J Biol Chem. 2001, 276 (22): 18934-18940. 10.1074/jbc.M101103200.CrossRefPubMed
27.
Huang XY, Wang HC, Yuan Z, Li A, He ML, Ai KX, Zheng Q, Qin HL: Gemcitabine combined with gum mastic causes potent growth inhibition and apoptosis of pancreatic cancer cells. Acta Pharmacol Sin. 2010, 31 (6): 741-745. 10.1038/aps.2010.54.CrossRefPubMedPubMedCentral
28.
Kong R, Sun B, Jiang H, Pan S, Chen H, Wang S, Krissansen GW, Sun X: Downregulation of nuclear factor-kappaB p65 subunit by small interfering RNA synergizes with gemcitabine to inhibit the growth of pancreatic cancer. Cancer Lett. 2010, 291 (1): 90-98. 10.1016/j.canlet.2009.10.001.CrossRefPubMed
29.
Pan X, Arumugam T, Yamamoto T, Levin PA, Ramachandran V, Ji B, Lopez-Berestein G, Vivas-Mejia PE, Sood AK, McConkey DJ, Logsdon CD: Nuclear factor-kappaB p65/relA silencing induces apoptosis and increases gemcitabine effectiveness in a subset of pancreatic cancer cells. Clin Cancer Res. 2008, 14 (24): 8143-8151. 10.1158/1078-0432.CCR-08-1539.CrossRefPubMedPubMedCentral
30.
Uwagawa T, Chiao PJ, Gocho T, Hirohara S, Misawa T, Yanaga K: Combination chemotherapy of nafamostat mesilate with gemcitabine for pancreatic cancer targeting NF-kappaB activation. Anticancer Res. 2009, 29 (8): 3173-3178.PubMed
31.
Beloussow K, Wang L, Wu J, Ann D, Shen WC: Recombinant arginine deiminase as a potential anti-angiogenic agent. Cancer Lett. 2002, 183 (2): 155-162. 10.1016/S0304-3835(01)00793-5.CrossRefPubMed
32.
Miyazaki K, Takaku H, Umeda M, Fujita T, Huang WD, Kimura T, Yamashita J, Horio T: Potent growth inhibition of human tumor cells in culture by arginine deiminase purified from a culture medium of a Mycoplasma-infected cell line. Cancer Res. 1990, 50 (15): 4522-4527.PubMed
33.
Zhang D, Ma QY, Hu HT, Zhang M: beta2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFkappaB and AP-1. Cancer Biol Ther. 2010, 10 (1): 19-29. 10.4161/cbt.10.1.11944.CrossRefPubMed
34.
Likhite N, Warawdekar UM: A unique method for isolation and solubilization of proteins after extraction of RNA from tumor tissue using trizol. J Biomol Tech. 2011, 22 (1): 37-44.PubMedPubMedCentral
35.
Liu H, Ma Q, Li J: High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem. 2011, 347 (1–2): 95-101.CrossRefPubMed
36.
Albrethsen J, Bogebo R, Gammeltoft S, Olsen J, Winther B, Raskov H: Upregulated expression of human neutrophil peptides 1, 2 and 3 (HNP 1–3) in colon cancer serum and tumours: a biomarker study. BMC Cancer. 2005, 5: 8-10.1186/1471-2407-5-8.CrossRefPubMedPubMedCentral
37.
Dillon BJ, Prieto VG, Curley SA, Ensor CM, Holtsberg FW, Bomalaski JS, Clark MA: Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation. Cancer. 2004, 100 (4): 826-833. 10.1002/cncr.20057.CrossRefPubMed
38.
Delage B, Fennell DA, Nicholson L, McNeish I, Lemoine NR, Crook T, Szlosarek PW: Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int J Cancer. 2010, 126 (12): 2762-2772.PubMed
39.
Hu J, Nakano H, Sakurai H, Colburn NH: Insufficient p65 phosphorylation at S536 specifically contributes to the lack of NF-kappaB activation and transformation in resistant JB6 cells. Carcinogenesis. 2004, 25 (10): 1991-2003. 10.1093/carcin/bgh198.CrossRefPubMed
40.
Jiang X, Takahashi N, Matsui N, Tetsuka T, Okamoto T: The NF-kappa B activation in lymphotoxin beta receptor signaling depends on the phosphorylation of p65 at serine 536. J Biol Chem. 2003, 278 (2): 919-926. 10.1074/jbc.M208696200.CrossRefPubMed
41.
Gong H, Pottgen C, Stuben G, Havers W, Stuschke M, Schweigerer L: Arginine deiminase and other antiangiogenic agents inhibit unfavorable neuroblastoma growth: potentiation by irradiation. Int J Cancer. 2003, 106 (5): 723-728. 10.1002/ijc.11298.CrossRefPubMed
42.
Park IS, Kang SW, Shin YJ, Chae KY, Park MO, Kim MY, Wheatley DN, Min BH: Arginine deiminase: a potential inhibitor of angiogenesis and tumour growth. Br J Cancer. 2003, 89 (5): 907-914. 10.1038/sj.bjc.6601181.CrossRefPubMedPubMedCentral
43.
Noh EJ, Kang SW, Shin YJ, Choi SH, Kim CG, Park IS, Wheatley DN, Min BH: Arginine deiminase enhances dexamethasone-induced cytotoxicity in human T-lymphoblastic leukemia CCRF-CEM cells. Int J Cancer. 2004, 112 (3): 502-508. 10.1002/ijc.20435.CrossRefPubMed
44.
Muerkoster S, Arlt A, Witt M, Gehrz A, Haye S, March C, Grohmann F, Wegehenkel K, Kalthoff H, Folsch UR, Schafer H: Usage of the NF-kappaB inhibitor sulfasalazine as sensitizing agent in combined chemotherapy of pancreatic cancer. Int J Cancer. 2003, 104 (4): 469-476. 10.1002/ijc.10963.CrossRefPubMed
45.
Greten FR, Weber CK, Greten TF, Schneider G, Wagner M, Adler G, Schmid RM: Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis. Gastroenterology. 2002, 123 (6): 2052-2063. 10.1053/gast.2002.37075.CrossRefPubMed
46.
Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB: Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007, 67 (8): 3853-3861. 10.1158/0008-5472.CAN-06-4257.CrossRefPubMed
47.
Liptay S, Weber CK, Ludwig L, Wagner M, Adler G, Schmid RM: Mitogenic and antiapoptotic role of constitutive NF-kappaB/Rel activity in pancreatic cancer. Int J Cancer. 2003, 105 (6): 735-746. 10.1002/ijc.11081.CrossRefPubMed
48.
Xiong HQ, Abbruzzese JL, Lin E, Wang L, Zheng L, Xie K: NF-kappaB activity blockade impairs the angiogenic potential of human pancreatic cancer cells. Int J Cancer. 2004, 108 (2): 181-188. 10.1002/ijc.11562.CrossRefPubMed
49.
Yebra M, Filardo EJ, Bayna EM, Kawahara E, Becker JC, Cheresh DA: Induction of carcinoma cell migration on vitronectin by NF-kappa B-dependent gene expression. Mol Biol Cell. 1995, 6 (7): 841-850. 10.1091/mbc.6.7.841.CrossRefPubMedPubMedCentral
50.
Loercher A, Lee TL, Ricker JL, Howard A, Geoghegen J, Chen Z, Sunwoo JB, Sitcheran R, Chuang EY, Mitchell JB, Baldwin AJ, Van Waes C: Nuclear factor-kappaB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res. 2004, 64 (18): 6511-6523. 10.1158/0008-5472.CAN-04-0852.CrossRefPubMed
51.
Ludwig L, Kessler H, Wagner M, Hoang-Vu C, Dralle H, Adler G, Bohm BO, Schmid RM: Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation. Cancer Res. 2001, 61 (11): 4526-4535.PubMed
52.
Maldonado V, Melendez-Zajgla J, Ortega A: Modulation of NF-kappa B, and Bcl-2 in apoptosis induced by cisplatin in HeLa cells. Mutat Res. 1997, 381 (1): 67-75. 10.1016/S0027-5107(97)00150-4.CrossRefPubMed
53.
Armstrong MB, Bian X, Liu Y, Subramanian C, Ratanaproeksa AB, Shao F, Yu VC, Kwok RP, Opipari AW, Castle VP: Signaling from p53 to NF-kappa B determines the chemotherapy responsiveness of neuroblastoma. Neoplasia. 2006, 8 (11): 964-974.CrossRefPubMedPubMedCentral
54.
Weng CJ, Chau CF, Hsieh YS, Yang SF, Yen GC: Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-kappaB and AP-1. Carcinogenesis. 2008, 29 (1): 147-156.CrossRefPubMed
Metadata
Title
Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling
Authors
Jiangbo Liu
Jiguang Ma
Zheng Wu
Wei Li
Dong Zhang
Liang Han
Fengfei Wang
Katie M Reindl
Erxi Wu
Qingyong Ma
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-686

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

What do women with gynecologic cancer know about HPV and their individual disease? A pilot study

Research article

18F-FDG PET/CT oncologic imaging at extended injection-to-scan acquisition time intervals derived from a single-institution 18F-FDG-directed surgery experience: feasibility and quantification of 18F-FDG accumulation within 18F-FDG-avid lesions and background tissues

Research article

Metformin induces an intracellular reductive state that protects oesophageal squamous cell carcinoma cells against cisplatin but not copper-bis(thiosemicarbazones)

Research article

Cost-utility analysis of maintenance therapy with gemcitabine or erlotinib vsobservation with predefined second-line treatment after cisplatin–gemcitabine induction chemotherapy for advanced NSCLC: IFCT-GFPC 0502-Eco phase III study

Research article

Remodeling of the pulmonary artery induced by metastatic gastric carcinoma: a histopathological analysis of 51 autopsy cases

Research article

Diagnosis and staging of superficial esophageal precursor based on pre-endoscopic resection system comparable to endoscopic resection
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