S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer
Abstract Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustain...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05289-4 |
| _version_ | 1811226926111522816 |
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| author | Fakiha Firdaus Manish Kuchakulla Rehana Qureshi Raul Ariel Dulce Yash Soni Derek J. Van Booven Khushi Shah Thomas Masterson Omar Joel Rosete Sanoj Punnen Joshua M. Hare Ranjith Ramasamy Himanshu Arora |
| author_facet | Fakiha Firdaus Manish Kuchakulla Rehana Qureshi Raul Ariel Dulce Yash Soni Derek J. Van Booven Khushi Shah Thomas Masterson Omar Joel Rosete Sanoj Punnen Joshua M. Hare Ranjith Ramasamy Himanshu Arora |
| author_sort | Fakiha Firdaus |
| collection | DOAJ |
| description | Abstract Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients. |
| first_indexed | 2024-04-12T09:32:57Z |
| format | Article |
| id | doaj.art-e2dd2463f7454636b871a42fa1edf315 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-12T09:32:57Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-e2dd2463f7454636b871a42fa1edf3152022-12-22T03:38:19ZengNature Publishing GroupCell Death and Disease2041-48892022-10-01131011310.1038/s41419-022-05289-4S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancerFakiha Firdaus0Manish Kuchakulla1Rehana Qureshi2Raul Ariel Dulce3Yash Soni4Derek J. Van Booven5Khushi Shah6Thomas Masterson7Omar Joel Rosete8Sanoj Punnen9Joshua M. Hare10Ranjith Ramasamy11Himanshu Arora12Department of Urology, Miller School of Medicine, University of MiamiDepartment of Urology, Miller School of Medicine, University of MiamiJohn P Hussman Institute for Human Genomics, Miller School of Medicine, University of MiamiThe Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of MiamiDepartment of Urology, Miller School of Medicine, University of MiamiJohn P Hussman Institute for Human Genomics, Miller School of Medicine, University of MiamiDepartment of Urology, Miller School of Medicine, University of MiamiDepartment of Urology, Miller School of Medicine, University of MiamiDepartment of Urology, Miller School of Medicine, University of MiamiDepartment of Urology, Miller School of Medicine, University of MiamiJohn P Hussman Institute for Human Genomics, Miller School of Medicine, University of MiamiDepartment of Urology, Miller School of Medicine, University of MiamiDepartment of Urology, Miller School of Medicine, University of MiamiAbstract Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.https://doi.org/10.1038/s41419-022-05289-4 |
| spellingShingle | Fakiha Firdaus Manish Kuchakulla Rehana Qureshi Raul Ariel Dulce Yash Soni Derek J. Van Booven Khushi Shah Thomas Masterson Omar Joel Rosete Sanoj Punnen Joshua M. Hare Ranjith Ramasamy Himanshu Arora S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer Cell Death and Disease |
| title | S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer |
| title_full | S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer |
| title_fullStr | S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer |
| title_full_unstemmed | S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer |
| title_short | S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer |
| title_sort | s nitrosylation of csf1 receptor increases the efficacy of csf1r blockage against prostate cancer |
| url | https://doi.org/10.1038/s41419-022-05289-4 |
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