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ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Translational Pharmacology
Volume 15 - 2024 |
doi: 10.3389/fphar.2024.1482354
Inhibition of CISD2 Enhances Sensitivity in Diffuse Large B-cell Lymphoma by Regulating Ferroptosis and Ferritinophagy
Provisionally accepted- 1 Affiliated Hospital of Putian University, Putian, China
- 2 Putian University, Putian, Fujian Province, China
- 3 Quanzhou First Hospital, Fujian Medical University, Quanzhou, Fujian Province, China
Background CDGSH iron-sulfur domain 2 (CISD2), an iron-sulfur protein with a [2Fe-2S] cluster, plays a pivotal role in the progression of various cancers, including Diffuse Large B-cell Lymphoma (DLBCL). However, the mechanisms by which CISD2 regulates the occurrence and development of DLBCL remain to be fully elucidated. Methods The potential role of CISD2 as a predictive marker in DLBCL patients treated with the R-CHOP regimen was investigated through bioinformatics analysis and clinical cohort studies. DLBCL cell lines (SUDHL-4 and HBL-1) were employed in this research. Adenoviral (AV) plasmids were used to either silence or overexpress CISD2 in these DLBCL cell lines. Additionally, the induction of ferroptosis in DLBCL cell lines was assessed. Various parameters, including cell proliferation, intracellular free iron levels, lipid peroxides, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP), were measured. Furthermore, the expression of proteins associated with ferroptosis and ferritinophagy was analyzed. Drug-resistant DLBCL cell lines were developed by gradually increasing doxorubicin (DOX) concentration over six months. The biological role of CISD2 in these drug-resistant DLBCL cell lines was subsequently assessed. Results Elevated CISD2 levels were found to be associated with decreased sensitivity of DLBCL patients to the R-CHOP regimen, as indicated by bioinformatics and clinical cohort analysis. Silencing CISD2 significantly reduced cell proliferation, increased iron accumulation, depleted glutathione (GSH), and elevated malondialdehyde (MDA) levels, alongside the accumulation of ROS and increased MMP. Additionally, BECN1 and NCOA4 expressions were upregulated, while p62, FTH1, and GPX4 expressions were downregulated. Conversely, overexpression of CISD2 reversed these effects. Treatment of DLBCL cell lines with Erastin led to decreased CISD2 levels. Notably, in drug-resistant DLBCL cell lines, CISD2 knockdown promoted ferroptosis and ferritinophagy, restoring sensitivity to DOX and enhancing the efficacy of Erastin treatment. Conclusion Our findings suggest that CISD2 may play a role in the drug resistance observed in DLBCL patients. Inhibition of CISD2 could enhance ferroptosis and ferritinophagy, potentially improving the sensitivity of DLBCL cells to DOX treatment.
Keywords: Diffuse large B-cell lymphoma, CDGSH iron sulfur domain 2, ferroptosis, Ferritinophagy, Drug Resistance
Received: 18 Aug 2024; Accepted: 29 Oct 2024.
Copyright: © 2024 ZHANG, ZHAN, HE, PAN, YOU, Lin and ZHU. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Qi Lin, Affiliated Hospital of Putian University, Putian, China
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