S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer.
Fakiha FirdausManish KuchakullaRehana QureshiRaul Ariel DulceYash SoniDerek J Van BoovenKhushi ShahThomas MastersonOmar Joel RoseteSanoj PunnenJoshua M HareRanjith RamasamyHimanshu AroraPublished in: Cell death & disease (2022)
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.
Keyphrases
- nitric oxide synthase
- nitric oxide
- prostate cancer
- oxidative stress
- cerebrospinal fluid
- high grade
- end stage renal disease
- type diabetes
- hydrogen peroxide
- chronic kidney disease
- endothelial cells
- metabolic syndrome
- clinical trial
- peritoneal dialysis
- skeletal muscle
- acute myeloid leukemia
- open label
- mouse model
- low grade
- ejection fraction
- patient reported outcomes
- newly diagnosed
- men who have sex with men
- microbial community
- insulin resistance
- cell death
- long non coding rna
- endoplasmic reticulum stress
- fluorescent probe
- anaerobic digestion
- glycemic control
- antiretroviral therapy
- prognostic factors
- hiv testing