Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma
Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body’s surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/1/76 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832588884528070656 |
|---|---|
| author | Nadia St. Thomas Benjamin N. Christopher Leticia Reyes Reeder M. Robinson Lena Golick Xiaoyi Zhu Eli Chapman Nathan G. Dolloff |
| author_facet | Nadia St. Thomas Benjamin N. Christopher Leticia Reyes Reeder M. Robinson Lena Golick Xiaoyi Zhu Eli Chapman Nathan G. Dolloff |
| author_sort | Nadia St. Thomas |
| collection | DOAJ |
| description | Cutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body’s surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induction of the HSP70 family member <i>HSPA6</i> (HSP70B’) and, to a lesser extent, <i>HSPA5</i> (BiP/GRP78). To understand the significance of these two factors, we used a novel isoform selective small-molecule inhibitor of HSPA5/6 (JG-023). JG-023 induced pro-apoptotic UPR signaling and enhanced the cytotoxic effects of proteasome inhibitors and other UPR-inducing drugs in CTCL but not normal T cells. Interestingly, JG-023 also selectively suppressed the production of Th2 cytokines in CTCL and normal CD4+ T cells. Conditioned media (CM) from CTCL were immunosuppressive to normal T cells through an IL-10-dependent mechanism. This immunosuppression could be reversed by JG-023, other HSP70 inhibitors, Btz, and combinations of these UPR-targeted drugs. Our study points to the importance of the UPR in the pathology of CTCL and demonstrates the potential of proteasome and targeted HSPA5/6 inhibitors for therapy. |
| format | Article |
| id | doaj-art-1689007554184a3886e8d6b91c462e09 |
| institution | Kabale University |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-1689007554184a3886e8d6b91c462e092025-01-24T13:25:05ZengMDPI AGBiomolecules2218-273X2025-01-011517610.3390/biom15010076Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell LymphomaNadia St. Thomas0Benjamin N. Christopher1Leticia Reyes2Reeder M. Robinson3Lena Golick4Xiaoyi Zhu5Eli Chapman6Nathan G. Dolloff7Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USADepartment of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USADepartment of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USADepartment of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USADepartment of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USADepartment of Pharmacology and Therapeutics, Center for Inflammation Science and Systems Medicine, University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USADepartment of Pharmacology and Therapeutics, Center for Inflammation Science and Systems Medicine, University of Florida Scripps Institute for Biomedical Innovation and Technology, Jupiter, FL 33458, USADepartment of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Ave., MSC509, Charleston, SC 29425, USACutaneous T-cell lymphoma (CTCL) is a rare T-cell malignancy characterized by inflamed and painful rash-like skin lesions that may affect large portions of the body’s surface. Patients experience recurrent infections due to a compromised skin barrier and generalized immunodeficiency resulting from a dominant Th2 immune phenotype of CTCL cells. Given the role of the unfolded protein response (UPR) in normal and malignant T-cell development, we investigated the impact of UPR-inducing drugs on the viability, transcriptional networks, and Th2 phenotype of CTCL. We found that CTCL cells were >5-fold more sensitive to the proteasome inhibitor bortezomib (Btz) and exhibited a distinct signaling and transcriptional response compared to normal CD4+ cells. The CTCL response was dominated by the induction of the HSP70 family member <i>HSPA6</i> (HSP70B’) and, to a lesser extent, <i>HSPA5</i> (BiP/GRP78). To understand the significance of these two factors, we used a novel isoform selective small-molecule inhibitor of HSPA5/6 (JG-023). JG-023 induced pro-apoptotic UPR signaling and enhanced the cytotoxic effects of proteasome inhibitors and other UPR-inducing drugs in CTCL but not normal T cells. Interestingly, JG-023 also selectively suppressed the production of Th2 cytokines in CTCL and normal CD4+ T cells. Conditioned media (CM) from CTCL were immunosuppressive to normal T cells through an IL-10-dependent mechanism. This immunosuppression could be reversed by JG-023, other HSP70 inhibitors, Btz, and combinations of these UPR-targeted drugs. Our study points to the importance of the UPR in the pathology of CTCL and demonstrates the potential of proteasome and targeted HSPA5/6 inhibitors for therapy.https://www.mdpi.com/2218-273X/15/1/76cutaneous T-cell lymphomaER stressunfolded protein responsebortezomibHSP70HSPA5 |
| spellingShingle | Nadia St. Thomas Benjamin N. Christopher Leticia Reyes Reeder M. Robinson Lena Golick Xiaoyi Zhu Eli Chapman Nathan G. Dolloff Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma Biomolecules cutaneous T-cell lymphoma ER stress unfolded protein response bortezomib HSP70 HSPA5 |
| title | Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma |
| title_full | Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma |
| title_fullStr | Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma |
| title_full_unstemmed | Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma |
| title_short | Pharmacological Modulation of the Unfolded Protein Response as a Therapeutic Approach in Cutaneous T-Cell Lymphoma |
| title_sort | pharmacological modulation of the unfolded protein response as a therapeutic approach in cutaneous t cell lymphoma |
| topic | cutaneous T-cell lymphoma ER stress unfolded protein response bortezomib HSP70 HSPA5 |
| url | https://www.mdpi.com/2218-273X/15/1/76 |
| work_keys_str_mv | AT nadiastthomas pharmacologicalmodulationoftheunfoldedproteinresponseasatherapeuticapproachincutaneoustcelllymphoma AT benjaminnchristopher pharmacologicalmodulationoftheunfoldedproteinresponseasatherapeuticapproachincutaneoustcelllymphoma AT leticiareyes pharmacologicalmodulationoftheunfoldedproteinresponseasatherapeuticapproachincutaneoustcelllymphoma AT reedermrobinson pharmacologicalmodulationoftheunfoldedproteinresponseasatherapeuticapproachincutaneoustcelllymphoma AT lenagolick pharmacologicalmodulationoftheunfoldedproteinresponseasatherapeuticapproachincutaneoustcelllymphoma AT xiaoyizhu pharmacologicalmodulationoftheunfoldedproteinresponseasatherapeuticapproachincutaneoustcelllymphoma AT elichapman pharmacologicalmodulationoftheunfoldedproteinresponseasatherapeuticapproachincutaneoustcelllymphoma AT nathangdolloff pharmacologicalmodulationoftheunfoldedproteinresponseasatherapeuticapproachincutaneoustcelllymphoma |