Pancreatic Cancer-Specific Cell Death Induced In Vivo by Cytoplasmic-Delivered Polyinosine-Polycytidylic Acid

被引：38

作者：

Bhoopathi, Praveen ^{[1
]}

Quinn, Bridget A. ^{[1
]}

Gui, Qin ^{[1
]}

Shen, Xue-Ning ^{[1
]}

Grossman, Steven R. ^{[1
,2
,3
]}

Das, Swadesh K. ^{[1
,4
]}

Sarkar, Devanand ^{[1
,3
,4
]}

Fisher, Paul B. ^{[1
,3
,4
]}

Emdad, Luni ^{[1
,3
,4
]}

机构：

[1] Virginia Commonwealth Univ, Sch Med, Dept Human & Mol Genet, Richmond, VA USA

[2] Virginia Commonwealth Univ, Dept Internal Med, Sch Med, Richmond, VA USA

[3] Virginia Commonwealth Univ, VCU Massey Canc Ctr, Sch Med, Richmond, VA USA

[4] Virginia Commonwealth Univ, Sch Med, VCU Inst Mol Med, Richmond, VA USA

来源：

CANCER RESEARCH | 2014年 / 74卷 / 21期

关键词：

DOUBLE-STRANDED-RNA; X-LINKED INHIBITOR; GENE-THERAPY CGT; AKT PHOSPHORYLATION; PERILLYL ALCOHOL; CARCINOMA CELLS; RIG-I; PROTEIN EXPRESSION; RECEPTOR AGONISTS; INNATE IMMUNITY;

D O I：

10.1158/0008-5472.CAN-14-0819

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Polyinosine-polycytidylic acid [pIC] is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and natural killer cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells (PDAC) but its mechanism of action is obscure. In this study, we investigated the potential therapeutic activity of a formulation of pIC with polyethylenimine ([pIC](PEI)) in PDAC and investigated its mechanism of action. [pIC](PEI) stimulated apoptosis in PDAC cells without affecting normal pancreatic epithelial cells. Mechanistically, [pIC](PEI) repressed XIAP and survivin expression and activated an immune response by inducing MDA-5, RIG-I, and NOXA. Phosphorylation of AKT was inhibited by [pIC](PEI) in PDAC, and this event was critical for stimulating apoptosis through XIAP and survivin degradation. In vivo administration of [pIC](PEI) inhibited tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic models of PDAC. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC](PEI) as an immunochemotherapy to treat pancreatic cancer. (C) 2014 AACR.

引用

页码：6224 / 6235

页数：12

共 53 条

[1]

Toll-like receptor agonists in cancer therapy [J].

Adams, Sylvia .

IMMUNOTHERAPY, 2009, 1 (06) :949-964

[2]

Al Haddad AH, 2014, EXPERT OPIN INV DRUG, V7, P1

[3]

Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[4]

Validating survivin as a cancer therapeutic target [J].

Altieri, DC .

NATURE REVIEWS CANCER, 2003, 3 (01) :46-54

[5]

Akt pathway protein expression in gastrointestinal Kaposi sarcomas: relevance for tumor biology [J].

Badescu, Alina ;

Couvelard, Anne ;

Handra-Luca, Adriana .

APMIS, 2014, 122 (06) :518-525

[6]

Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: Key regulators of innate immunity [J].

Barral, Paola M. ;

Sarkar, Devanand ;

Su, Zao-zhong ;

Barber, Glen N. ;

DeSalle, Rob ;

Racaniello, Vincent R. ;

Fisher, Paul B. .

PHARMACOLOGY & THERAPEUTICS, 2009, 124 (02) :219-234

[7]

Protein kinase Cε makes the life and death decision [J].

Basu, Alakananda ;

Sivaprasad, Usha .

CELLULAR SIGNALLING, 2007, 19 (08) :1633-1642

[8]

Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells [J].

Besch, Robert ;

Poeck, Hendrik ;

Hohenauer, Tobias ;

Senft, Daniela ;

Haecker, Georg ;

Berking, Carola ;

Hornung, Veit ;

Endres, Stefan ;

Ruzicka, Thomas ;

Rothenfusser, Simon ;

Hartmann, Gunther .

JOURNAL OF CLINICAL INVESTIGATION, 2009, 119 (08) :2399-2411

[9]

Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression [J].

Bhang, Hyo-eun C. ;

Gabrielson, Kathleen L. ;

Laterra, John ;

Fisher, Paul B. ;

Pomper, Martin G. .

NATURE MEDICINE, 2011, 17 (01) :123-U302

[10]

RETRACTED: Blockade of tumor growth due to matrix metalloproteinase-9 inhibition is mediated by sequential activation of β1-integrin, ERK, and NF-κB (Retracted article. See vol. 295, pg. 15426, 2020) [J].

Bhoopathi, Praveen ;

Chetty, Chandramu ;

Kunigal, Sateesh ;

Vanamala, Sravan K. ;

Rao, Jasti S. ;

Lakka, Sajani S. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (03) :1545-1552

← 1 2 3 4 5 6 →