PD03-06: Mitochondrial complex I protein NDUFS3 is decreased in benign prostatic hyperplasia patients treated with celecoxib and/or finasteride.
Friday, May 3, 2024 7:50 AM to 8:00 AM · 10 min. (US/Central)
303A
Abstract
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Full Abstract and Figures
Author Block
Chandler N Hudson*, Springfield, IL, Teresa T Liu, Madison, WI, Taro Igarashi, Nathalie El-Khoury, Nnamdi Ihejirika, Kelsey Paxton, Juliann Jaumotte, Rajiv Dhir, Joel B Nelson, Donald B DeFranco, Pittsburgh, PA, William A Ricke, Madison, WI, Naoki Yoshimura, Zhou Wang, Laura E Pascal, Pittsburgh, PA
Introduction
Benign prostatic hyperplasia (BPH) is treated with multiple medical therapies and surgical options with variable outcomes. Some of the heterogeneity in treatment efficacy may come from an incomplete understanding of their molecular and cellular impact. A decline in essential mitochondrial protein expression has been observed in BPH tissues, suggesting mitochondrial dysfunction may be a factor in BPH pathogenesis. Both finasteride and celecoxib have been associated with mitochondrial toxicity in other tissues. The objective of this study was to determine whether the BPH therapies finasteride and celecoxib might impact mitochondrial function in prostate tissues, specifically their effects on NDUFS3.
Methods
NDUFS3, E-cadherin and inflammatory cell immunostaining were performed on simple prostatectomy BPH specimens from patients naïve to androgen manipulation who were treated with celecoxib and/or finasteride for 28 days in a four-arm, phase II randomized, single-blind clinical trial. NDUFS3 and inflammatory cell staining was also conducted in a murine model of celecoxib treatment in male mice. Quantification analyses of immunostaining were performed.
Results
NDUFS3 was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3, and however there was no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration.
Conclusions
These findings suggest that celecoxib and/or finasteride are associated with a decline in NDUFS3 in prostate tissues but no change in inflammatory cell infiltration. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, therapeutic targeting of BPH with celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in BPH patients. Future development of therapeutic strategies improving mitochondrial function may improve the efficacy of celecoxib and/or finasteride in BPH patients.
Source Of Funding
This work was funded in part by NIH grants K01 AG059899 from NIA to TL; U54 DK104310, R01 DK131175, and R01 DK127081 from NIDDK to WAR; U54 DK112079 and R56 DK107492 from NIDDK to ZW; and CAIRIBU Convergence Award to LEP from NIDDK. This project also used the Pitt Biospecimen Core and was supported in part by award P30CA047904.
Author Block
Chandler N Hudson*, Springfield, IL, Teresa T Liu, Madison, WI, Taro Igarashi, Nathalie El-Khoury, Nnamdi Ihejirika, Kelsey Paxton, Juliann Jaumotte, Rajiv Dhir, Joel B Nelson, Donald B DeFranco, Pittsburgh, PA, William A Ricke, Madison, WI, Naoki Yoshimura, Zhou Wang, Laura E Pascal, Pittsburgh, PA
Introduction
Benign prostatic hyperplasia (BPH) is treated with multiple medical therapies and surgical options with variable outcomes. Some of the heterogeneity in treatment efficacy may come from an incomplete understanding of their molecular and cellular impact. A decline in essential mitochondrial protein expression has been observed in BPH tissues, suggesting mitochondrial dysfunction may be a factor in BPH pathogenesis. Both finasteride and celecoxib have been associated with mitochondrial toxicity in other tissues. The objective of this study was to determine whether the BPH therapies finasteride and celecoxib might impact mitochondrial function in prostate tissues, specifically their effects on NDUFS3.
Methods
NDUFS3, E-cadherin and inflammatory cell immunostaining were performed on simple prostatectomy BPH specimens from patients naïve to androgen manipulation who were treated with celecoxib and/or finasteride for 28 days in a four-arm, phase II randomized, single-blind clinical trial. NDUFS3 and inflammatory cell staining was also conducted in a murine model of celecoxib treatment in male mice. Quantification analyses of immunostaining were performed.
Results
NDUFS3 was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3, and however there was no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration.
Conclusions
These findings suggest that celecoxib and/or finasteride are associated with a decline in NDUFS3 in prostate tissues but no change in inflammatory cell infiltration. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, therapeutic targeting of BPH with celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in BPH patients. Future development of therapeutic strategies improving mitochondrial function may improve the efficacy of celecoxib and/or finasteride in BPH patients.
Source Of Funding
This work was funded in part by NIH grants K01 AG059899 from NIA to TL; U54 DK104310, R01 DK131175, and R01 DK127081 from NIDDK to WAR; U54 DK112079 and R56 DK107492 from NIDDK to ZW; and CAIRIBU Convergence Award to LEP from NIDDK. This project also used the Pitt Biospecimen Core and was supported in part by award P30CA047904.