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Hokkaido University Collection of Scholarly and Academic Papers >
Graduate School of Medicine / Faculty of Medicine >
Peer-reviewed Journal Articles, etc >
PolyI:C-Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector-Mediated Tumor Elimination In Vivo
| Title: | PolyI:C-Induced, TLR3/RIP3-Dependent Necroptosis Backs Up Immune Effector-Mediated Tumor Elimination In Vivo |
| Other Titles: | TICAM-1-RIP3 necroptosis in tumor |
| Authors: | Takemura, Ryo Browse this author | | Takaki, Hiromi Browse this author | | Okada, Seiji Browse this author →KAKEN DB | | Shime, Hiroaki Browse this author →KAKEN DB | | Akazawa, Takashi Browse this author →KAKEN DB | | Oshiumi, Hiroyuki Browse this author →KAKEN DB | | Matsumoto, Misako Browse this author →KAKEN DB | | Teshima, Takanori Browse this author →KAKEN DB | | Seya, Tsukasa Browse this author →KAKEN DB |
| Keywords: | RNA (polyI:C) | | TLR3 | | TICAM-1 | | necroptosis | | RIP kinases |
| Issue Date: | Aug-2015 |
| Publisher: | American Association for Cancer Research |
| Journal Title: | Cancer immunology research |
| Volume: | 3 |
| Issue: | 8 |
| Start Page: | 902 |
| End Page: | 914 |
| Publisher DOI: | 10.1158/2326-6066.CIR-14-0219 |
| PMID: | 25898986 |
| Abstract: | Double-stranded RNA directly acts on fibroblast and myeloid lineages to induce necroptosis as in TNFα. Here, we investigated whether this type of cell death occurred in cancer cells in response to polyinosinic-polycytidylic acid (polyI:C) and the pan-caspase inhibitor z-Val-Ala-Asp fluromethyl ketone (zVAD). We found that the colon cancer cell line CT26 is highly susceptible to necroptosis, as revealed by staining with annexin V/propidium iodide. CT26 cells possess RNA sensors, TLR3 and MDA5, which are upregulated by interferon (IFN)-inducing pathways and linked to receptor-interacting protein kinase (RIP) 1/3 activation via TICAM-1 or MAVS adaptor, respectively. Although exogenously added polyI:C alone marginally induced necroptosis in CT26 cells, a combined regimen of polyI:C and zVAD induced approximately 50% CT26 necroptosis in vitro without secondary effects of TNFα or type I IFNs. CT26 necroptosis depended on the TLR3-TICAM-1-RIP3 axis in the tumor cells to produce reactive oxygen species, but not on MDA5, MAVS, or the caspases/inflammasome activation. However, the RNA-derived necroptosis was barely reproduced in vivo in a CT26 tumor-implanted Balb/c mouse model with administration of polyI:C + zVAD. Significant shrinkage of CT26 tumors was revealed only when polyI:C (100 μg) was injected intraperitoneally and zVAD (1 mg) subcutaneously into tumor-bearing mice that were depleted of cytotoxic T lymphocytes and natural killer cells. The results were confirmed with immune-compromised mice with no lymphocytes. Although necroptosis-induced tumor growth retardation appears mechanistically complicated and dependent on the injection routes of polyI:C and zVAD, anti-caspase reagent directed to tumor cells will make RNA adjuvant immunotherapy more effective by modulating the formation of the tumoricidal microenvironment and dendritic cell-inducing antitumor immune system. |
| Type: | article (author version) |
| URI: | http://hdl.handle.net/2115/62581 |
| Appears in Collections: | 医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
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Submitter: 瀬谷 司
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