Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Antitumor Effect of Cycle Inhibiting Factor Expression in Colon Cancer via Salmonella VNP20009

Author(s): Liang Liu, Junhua Zhang, Mingqiang Gu, Guichao Li, Jianjiao Ni and Min Fan*

Volume 20 , Issue 14 , 2020

Page: [1722 - 1727] Pages: 6

DOI: 10.2174/1871520620666200423080622

Price: $65


Background: Colon cancer is one of the major causes of morbidity and mortality worldwide. Cycle inhibiting factors (Cifs) have been shown to deamidate Nedd8, resulting in cell cycle arrest.

Objective: To determine the antitumor effect of Cifs on colon cancer by using attenuated Salmonella typhimurium VNP20009.

Methods: The VNP-SOPE2-cif and VNP-SOPE2-cif-C/A plasmids were transfected into attenuated Salmonella typhimurium VNP20009. The efficiency and specificity of the Cif promoter were validated in colon cancer SW480 cell lines. Western blotting was subsequently performed to evaluate cell cycle regulators, including P21, P27 and Wee1. In vivo, the antitumor effect of VNP20009 was evaluated in a colon cancer xenograft model.

Results: Firstly, VNP-SOPE2-cif and VNP-SOPE2-cif-C/A were selectively expressed both in the bacterial and colon cancer cells. Cif expression in SW480 cells via the VNP tumor-targeted expression system induced the accumulation of Wee1, p21 and p27 expression. Moreover, tumor growth was significantly inhibited in the mice with VNP-SOPE2-cif compared to the mice with VNP with the empty construct.

Conclusion: These results suggest that Cif gene delivered by VNP20009 is a promising approach for the treatment of colon cancer.

Keywords: Cycle inhibiting factors, Salmonella, colon cancers, antitumor, plasmids, VNP-SOPE2-cif.

Graphical Abstract
Siegel, R.L.; Miller, K.D.; Jemal, A. J. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
Chen, W.; Sun, K.; Zheng, R. Cancer incidence and mortality in China, 2014. Chin. J. Cancer Res., 2018, 30(1), 1-12.
Nougayrède, J-P.; Boury, M.; Tasca, C.; Marchès, O.; Milon, A.; Oswald, E.; De Rycke, J. Type III secretion-dependent cell cycle block caused in HeLa cells by enteropathogenic Escherichia coli O103. Infect. Immun., 2001, 69(11), 6785-6795.
[] [PMID: 11598051]
Charpentier, X.; Oswald, E. Identification of the secretion and translocation domain of the enteropathogenic and enterohemorrhagic Escherichia coli effector Cif, using TEM-1 β-lactamase as a new fluorescence-based reporter. J. Bacteriol., 2004, 186(16), 5486-5495.
[]] [PMID: 15292151]
Marchès, O.; Ledger, T.N.; Boury, M.; Ohara, M.; Tu, X.; Goffaux, F.; Mainil, J.; Rosenshine, I.; Sugai, M.; De Rycke, J.; Oswald, E. Enteropathogenic and enterohaemorrhagic Escherichia coli deliver a novel effector called Cif, which blocks cell cycle G2/M transition. Mol. Microbiol., 2003, 50(5), 1553-1567.
[] [PMID: 14651638]
De Rycke, J.; Comtet, E.; Chalareng, C.; Boury, M.; Tasca, C.; Milon, A. Enteropathogenic Escherichia coli O103 from rabbit elicits actin stress fibers and focal adhesions in HeLa epithelial cells, cytopathic effects that are linked to an analog of the locus of enterocyte effacement. Infect. Immun., 1997, 65(7), 2555-2563.
[] [PMID: 9199419]
Samba-Louaka, A.; Nougayrède, J-P.; Watrin, C.; Oswald, E.; Taieb, F. The enteropathogenic Escherichia coli effector Cif induces delayed apoptosis in epithelial cells. Infect. Immun., 2009, 77(12), 5471-5477.
[] [PMID: 19786559]
Pérès, S.Y.; Marchès, O.; Daigle, F.; Nougayrède, J.P.; Herault, F.; Tasca, C.; De Rycke, J.; Oswald, E. A new cytolethal Distending Toxin (CDT) from Escherichia coli producing CNF2 blocks HeLa cell division in G2/M phase. Mol. Microbiol., 1997, 24(5), 1095-1107.
[] [PMID: 9220015]
Zhou, H.; Monack, D.M.; Kayagaki, N.; Wertz, I.; Yin, J.; Wolf, B.; Dixit, V.M. Yersinia virulence factor YopJ acts as a deubiquitinase to inhibit NF-κB activation. J. Exp. Med., 2005, 202(10), 1327-1332.
[] [PMID: 16301742]
Samba-Louaka, A.; Nougayrède, J.P.; Watrin, C.; Jubelin, G.; Oswald, E.; Taieb, F. Bacterial cyclomodulin Cif blocks the host cell cycle by stabilizing the cyclin-dependent kinase inhibitors p21 and p27. Cell. Microbiol., 2008, 10(12), 2496-2508.
[] [PMID: 18705694]
Liu, L.; Ni, J.; Zhang, J.; He, X. Construction and characterization of regulated cycle inhibiting factors induced upon Tet-On system in human colon cancer cell lines. Anticancer Drugs, 2018, 29(9), 854-860.
Leschner, S.; Weiss, S. Salmonella-allies in the fight against cancer. J. Mol. Med. (Berl.), 2010, 88(8), 763-773.
[] [PMID: 20526574]
Forbes, N.S. Engineering the perfect (bacterial) cancer therapy. Nat. Rev. Cancer, 2010, 10(11), 785-794.
[] [PMID: 20944664]
Zheng, L.M.; Luo, X.; Feng, M.; Li, Z.; Le, T.; Ittensohn, M.; Trailsmith, M.; Bermudes, D.; Lin, S.L.; King, I.C. Tumor amplified protein expression therapy: Salmonella as a tumor-selective protein delivery vector. Oncol. Res., 2000, 12(3), 127-135.
[] [PMID: 11216671]
Forbes, N.S.; Munn, L.L.; Fukumura, D.; Jain, R.K. Sparse initial entrapment of systemically injected Salmonella typhimurium leads to heterogeneous accumulation within tumors. Cancer Res., 2003, 63(17), 5188-5193.
[PMID: 14500342]
Clairmont, C.; Lee, K.C.; Pike, J.; Ittensohn, M.; Low, K.B.; Pawelek, J.; Bermudes, D.; Brecher, S.M.; Margitich, D.; Turnier, J.; Li, Z.; Luo, X.; King, I.; Zheng, L.M. Biodistribution and genetic stability of the novel antitumor agent VNP20009, a genetically modified strain of Salmonella typhimurium. J. Infect. Dis., 2000, 181(6), 1996-2002.
[] [PMID: 10837181]
Blache, C.A.; Manuel, E.R.; Kaltcheva, T.I.; Wong, A.N.; Ellenhorn, J.D.; Blazar, B.R.; Diamond, D.J. Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth. Cancer Res., 2012, 72(24), 6447-6456.
[] [PMID: 23090116]
Low, K.B.; Ittensohn, M.; Le, T.; Platt, J.; Sodi, S.; Amoss, M.; Ash, O.; Carmichael, E.; Chakraborty, A.; Fischer, J.; Lin, S.L.; Luo, X.; Miller, S.I.; Zheng, L.; King, I.; Pawelek, J.M.; Bermudes, D. Lipid A mutant Salmonella with suppressed virulence and TNFalpha induction retain tumor-targeting in vivo. Nat. Biotechnol., 1999, 17(1), 37-41.
[] [PMID: 9920266]
Liu, Z.; Liu, X.; Cao, W.; Hua, Z-C. Tumor-specifically hypoxia-induced therapy of SPRY1/2 displayed differential therapeutic efficacy for melanoma. Am. J. Cancer Res., 2015, 5(2), 792-801.
[PMID: 25973316]
Taieb, F.; Nougayrède, J.P.; Watrin, C.; Samba-Louaka, A.; Oswald, E. Escherichia coli cyclomodulin Cif induces G2 arrest of the host cell cycle without activation of the DNA-damage checkpoint-signalling pathway. Cell. Microbiol., 2006, 8(12), 1910-1921.
[] [PMID: 16848790]
Lee, C-H. Engineering bacteria toward tumor targeting for cancer treatment: Current state and perspectives. Appl. Microbiol. Biotechnol., 2012, 93(2), 517-523.
[] [PMID: 22120621]
Yoon, W.S.; Chae, Y.S.; Hong, J.; Park, Y.K. Antitumor therapeutic effects of a genetically engineered Salmonella typhimurium harboring TNF-α in mice. Appl. Microbiol. Biotechnol., 2011, 89(6), 1807-1819.
[] [PMID: 21113588]
Low, K.B.; Ittensohn, M.; Luo, X. Construction of VNP20009. Suicide Gene Therapy; Springer, 2004.
Broadway, K.M.; Modise, T.; Jensen, R.V.; Scharf, B.E. Complete genome sequence of Salmonella enterica serovar Typhimurium VNP20009, a strain engineered for tumor targeting. J. Biotechnol., 2014, 192(Pt A), 177-178.
[] [PMID: 25046822]
Ganai, S.; Arenas, R.B.; Sauer, J.P.; Bentley, B.; Forbes, N.S. In tumors Salmonella migrate away from vasculature toward the transition zone and induce apoptosis. Cancer Gene Ther., 2011, 18(7), 457-466.
[] [PMID: 21436868]
Zhao, C.; He, J.; Cheng, H.; Zhu, Z.; Xu, H. Enhanced therapeutic effect of an antiangiogenesis peptide on lung cancer in vivo combined with Salmonella VNP20009 carrying a Sox2 shRNA construct. J. Exp. Clin. Cancer Res., 2016, 35(1), 107.
[] [PMID: 27371094]
Zhou, B-B.S.; Elledge, S.J. The DNA damage response: Putting checkpoints in perspective. Nature, 2000, 408(6811), 433-439.
[] [PMID: 11100718]
Ng, M.Y.; Wang, M.; Casey, P.J.; Gan, Y-H.; Hagen, T. Activation of MAPK/ERK signaling by Burkholderia pseudomallei cycle inhibiting factor (Cif). PLoS One, 2017, 12(2)e0171464
[] [PMID: 28166272]
Jubelin, G.; Chavez, C.V.; Taieb, F.; Banfield, M.J.; Samba-Louaka, A.; Nobe, R.; Nougayrède, J.P.; Zumbihl, R.; Givaudan, A.; Escoubas, J.M.; Oswald, E. Cycle inhibiting factors (Cifs) are a growing family of functional cyclomodulins present in invertebrate and mammal bacterial pathogens. PLoS One, 2009, 4(3)e4855
[] [PMID: 19308257]
Watanabe, N.; Arai, H.; Iwasaki, J.; Shiina, M.; Ogata, K.; Hunter, T.; Osada, H. Cyclin-Dependent Kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways. Proc. Natl. Acad. Sci. USA, 2005, 102(33), 11663-11668.
[] [PMID: 16085715]
Chen, J.; Wei, D.; Zhuang, H. Proteomic screening of anaerobically regulated promoters from Salmonella and its antitumor applications. Mol. Cell. Proteomics, 2011, 10(6), M111-009399.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy