TY - JOUR
T1 - IPS-1 differentially induces TRAIL, BCL2, BIRC3 and PRKCE in type i interferons-dependent and-independent anticancer activity
AU - Kumar, S.
AU - Ingle, H.
AU - Mishra, S.
AU - Mahla, R. S.
AU - Kumar, A.
AU - Kawai, T.
AU - Akira, S.
AU - Takaoka, A.
AU - Raut, A. A.
AU - Kumar, H.
N1 - Funding Information:
Acknowledgements. We thank Dr Milind M Vaidya, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India for providing MCF10A cell line. We also thank Dr Toru Kubota, Department of Virology III, National Institute of Infectious Diseases, Tokyo, Japan for providing the construct of IRF3/5D. This work is partly supported by research grants SR/S2/RJN-55/2009 and BT/PR6009/GBD/27/382/2012 from Department of Science and technology (DST) and Department of Biotechnology (DBT), Government of India (HK); and Intramural Research Grant of IISER, Bhopal, India. This study was also partly supported by the Grant for Joint Research Program of the Institute for Genetic Medicine, Hokkaido University, Japan (HK and AT).
Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - RIG-I-like receptors are the key cytosolic sensors for RNA viruses and induce the production of type I interferons (IFN) and proinflammatory cytokines through a sole adaptor IFN-β promoter stimulator-1 (IPS-1) (also known as Cardif, MAVS and VISA) in antiviral innate immunity. These sensors also have a pivotal role in anticancer activity through induction of apoptosis. However, the mechanism for their anticancer activity is poorly understood. Here, we show that anticancer vaccine adjuvant, PolyIC (primarily sensed by MDA5) and the oncolytic virus, Newcastle disease virus (NDV) (sensed by RIG-I), induce anticancer activity. The ectopic expression of IPS-1 into type I IFN-responsive and non-responsive cancer cells induces anticancer activity. PolyIC transfection and NDV infection upregulate pro-apoptotic gene TRAIL and downregulate the anti-apoptotic genes BCL2, BIRC3 and PRKCE. Furthermore, stable knockdown of IPS-1, IRF3 or IRF7 in IFN-non-responsive cancer cells show reduced anticancer activity by suppressing apoptosis via TRAIL and anti-apoptotic genes. Collectively, our study shows that IPS-1 induces anticancer activity through upregulation of pro-apoptotic gene TRAIL and downregulation of the anti-apoptotic genes BCL2, BIRC3 and PRKCE via IRF3 and IRF7 in type I IFN-dependent and -independent manners.
AB - RIG-I-like receptors are the key cytosolic sensors for RNA viruses and induce the production of type I interferons (IFN) and proinflammatory cytokines through a sole adaptor IFN-β promoter stimulator-1 (IPS-1) (also known as Cardif, MAVS and VISA) in antiviral innate immunity. These sensors also have a pivotal role in anticancer activity through induction of apoptosis. However, the mechanism for their anticancer activity is poorly understood. Here, we show that anticancer vaccine adjuvant, PolyIC (primarily sensed by MDA5) and the oncolytic virus, Newcastle disease virus (NDV) (sensed by RIG-I), induce anticancer activity. The ectopic expression of IPS-1 into type I IFN-responsive and non-responsive cancer cells induces anticancer activity. PolyIC transfection and NDV infection upregulate pro-apoptotic gene TRAIL and downregulate the anti-apoptotic genes BCL2, BIRC3 and PRKCE. Furthermore, stable knockdown of IPS-1, IRF3 or IRF7 in IFN-non-responsive cancer cells show reduced anticancer activity by suppressing apoptosis via TRAIL and anti-apoptotic genes. Collectively, our study shows that IPS-1 induces anticancer activity through upregulation of pro-apoptotic gene TRAIL and downregulation of the anti-apoptotic genes BCL2, BIRC3 and PRKCE via IRF3 and IRF7 in type I IFN-dependent and -independent manners.
UR - http://www.scopus.com/inward/record.url?scp=84970925335&partnerID=8YFLogxK
U2 - 10.1038/cddis.2015.122
DO - 10.1038/cddis.2015.122
M3 - Article
C2 - 25950488
AN - SCOPUS:84970925335
SN - 2041-4889
VL - 6
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 5
M1 - e1758
ER -