Transcriptome and proteome profiling reveals stress-induced expression signatures of imiquimod-treated Tasmanian devil facial tumor disease (DFTD) cells
PDF | HTML | Supplementary Files | How to cite
Metrics: PDF 1548 views | HTML 2984 views | ?
Amanda L. Patchett1, Richard Wilson2, Jac C. Charlesworth1, Lynn M. Corcoran3,4, Anthony T. Papenfuss3,4,5,6, Bruce A. Lyons7, Gregory M. Woods1,7 and Cesar Tovar1
1Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia
2Central Science Laboratory, University of Tasmania, Hobart, Tasmania 7001, Australia
3Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia
4Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
5Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
6Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria 3000, Australia
7School of Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia
Amanda L. Patchett, email: [email protected]
Keywords: imiquimod; Tasmanian devil; devil facial tumor disease; cancer; immunotherapy
Received: November 09, 2017 Accepted: February 26, 2018 Published: March 23, 2018
As a topical cancer immunotherapy, the toll-like receptor 7 ligand imiquimod activates tumor regression via stimulation of immune cell infiltration and cytotoxic responses. Imiquimod also exerts direct pro-apoptotic effects on tumor cells in vitro, but a role for these effects in imiquimod-induced tumor regression remains undefined. We previously demonstrated that cell lines derived from devil facial tumor disease (DFTD), a transmissible cancer threatening the survival of the Tasmanian devil (Sarcophilus harrisii), are sensitive to imiquimod-induced apoptosis. In this study, the pro-apoptotic effects of imiquimod in DFTD have been investigated using RNA-sequencing and label-free quantitative proteomics. This analysis revealed that changes to gene and protein expression in imiquimod treated DFTD cells are consistent with the onset of oxidative and endoplasmic reticulum stress responses, and subsequent activation of the unfolded protein response, autophagy, cell cycle arrest and apoptosis. Imiquimod also regulates the expression of oncogenic pathways, providing a direct mechanism by which this drug may increase tumor susceptibility to immune cytotoxicity in vivo. Our study has provided the first global analysis of imiquimod-induced effects in any tumor cell line. These findings have highlighted the potential of cell stress pathways as therapeutic targets in DFTD, and will allow for improved mechanistic use of imiquimod as a therapy in both the Tasmanian devil and human cancers.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.