Cantharidin overcomes IL-2Rα signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species
BackgroundVorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30–35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms unde...
Saved in:
Published in | Journal for immunotherapy of cancer Vol. 12; no. 7; p. e009099 |
---|---|
Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
BMJ Publishing Group Ltd
14.07.2024
BMJ Publishing Group LTD BMJ Publishing Group |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | BackgroundVorinostat (SAHA) is a histone deacetylase inhibitor that has shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, only a subset of patients with CTCL (30–35%) respond to SAHA and the response is not always sustainable. Thus, understanding the mechanisms underlying evasive resistance in this cancer is an unmet medical need to improve the efficacy of current therapies.PurposeThis study aims to identify factors contributing to resistance against SAHA in CTCL and ways to mitigate it.Methods and resultsIn this study, we demonstrated that attenuated reactive oxygen species (ROS) induces the expression of interleukin (IL)-2Rα, one of the IL-2 receptors, which drives resistance to SAHA in CTCL. We also determined that cantharidin could overcome SAHA resistance to CTCL by blocking IL-2Rα-related signaling via ROS-dependent manner. Mechanistically, accelerated translation of IL-2Rα contributes to excessive IL-2Rα protein formation as a result of reduced ROS levels in SAHA-resistant CTCL. At the same time, amplified IL-2R signals are evidenced by strengthened interaction of IL-2Rβ with IL-2Rγ and Janus kinase/signal transducer and activator of transcription molecules, and by increased expression of protein kinase B (AKT)/mTOR and mitogen-activated protein kinase signaling. Moreover, cantharidin, an active constituent of Mylabris used in traditional Chinese medicine, markedly increased ROS levels, and thereby restrained IL-2Rα translation, resulting in suppression of downstream pathways in SAHA-resistant cells. Cantharidin is also found to synergize with SAHA and triggers SAHA-resistant cell death via IL-2R signaling both in vitro and in vivo.ConclusionOur study uncovers a novel molecular mechanism of acquired SAHA resistance and also suggests that using cantharidin is a potential approach to overcome CTCL therapy resistance. Our findings underlie the therapeutic potential of cantharidin in treating CTCL. |
---|---|
Bibliography: | Original research ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. Supplement: Additional supplemental material is published online only. To view, please visit the journal online (https://doi.org/10.1136/jitc-2024-009099). None declared. |
ISSN: | 2051-1426 2051-1426 |
DOI: | 10.1136/jitc-2024-009099 |