Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models

Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Rupert, Christofer [verfasserIn] Dell’ Aversana, Carmela Mosca, Laura Montanaro, Vittorino Arcaniolo, Davide De Sio, Marco Bilancio, Antonio Altucci, Lucia Palinski, Wulf Pili, Roberto de Nigris, Filomena

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Organoids Mitochondria Renal carcinoma Lysosomes Purinergic receptors Drug screening

Anmerkung:	© The Author(s) 2023. corrected publication 2023

Übergeordnetes Werk:	Enthalten in: Journal of experimental & clinical cancer research - Berlin : Springer, 2008, 42(2023), 1 vom: 26. Mai
Übergeordnetes Werk:	volume:42 ; year:2023 ; number:1 ; day:26 ; month:05

Links:	Volltext

DOI / URN:	10.1186/s13046-023-02713-1

Katalog-ID:	SPR051646854

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520			\|a Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy.
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allfields	10.1186/s13046-023-02713-1 doi (DE-627)SPR051646854 (SPR)s13046-023-02713-1-e DE-627 ger DE-627 rakwb eng Rupert, Christofer verfasserin aut Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023. corrected publication 2023 Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. Organoids (dpeaa)DE-He213 Mitochondria (dpeaa)DE-He213 Renal carcinoma (dpeaa)DE-He213 Lysosomes (dpeaa)DE-He213 Purinergic receptors (dpeaa)DE-He213 Drug screening (dpeaa)DE-He213 Dell’ Aversana, Carmela aut Mosca, Laura aut Montanaro, Vittorino aut Arcaniolo, Davide aut De Sio, Marco aut Bilancio, Antonio aut Altucci, Lucia aut Palinski, Wulf aut Pili, Roberto aut de Nigris, Filomena aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-023-02713-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 26 05
spelling	10.1186/s13046-023-02713-1 doi (DE-627)SPR051646854 (SPR)s13046-023-02713-1-e DE-627 ger DE-627 rakwb eng Rupert, Christofer verfasserin aut Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023. corrected publication 2023 Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. Organoids (dpeaa)DE-He213 Mitochondria (dpeaa)DE-He213 Renal carcinoma (dpeaa)DE-He213 Lysosomes (dpeaa)DE-He213 Purinergic receptors (dpeaa)DE-He213 Drug screening (dpeaa)DE-He213 Dell’ Aversana, Carmela aut Mosca, Laura aut Montanaro, Vittorino aut Arcaniolo, Davide aut De Sio, Marco aut Bilancio, Antonio aut Altucci, Lucia aut Palinski, Wulf aut Pili, Roberto aut de Nigris, Filomena aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-023-02713-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 26 05
allfields_unstemmed	10.1186/s13046-023-02713-1 doi (DE-627)SPR051646854 (SPR)s13046-023-02713-1-e DE-627 ger DE-627 rakwb eng Rupert, Christofer verfasserin aut Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023. corrected publication 2023 Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. Organoids (dpeaa)DE-He213 Mitochondria (dpeaa)DE-He213 Renal carcinoma (dpeaa)DE-He213 Lysosomes (dpeaa)DE-He213 Purinergic receptors (dpeaa)DE-He213 Drug screening (dpeaa)DE-He213 Dell’ Aversana, Carmela aut Mosca, Laura aut Montanaro, Vittorino aut Arcaniolo, Davide aut De Sio, Marco aut Bilancio, Antonio aut Altucci, Lucia aut Palinski, Wulf aut Pili, Roberto aut de Nigris, Filomena aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-023-02713-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 26 05
allfieldsGer	10.1186/s13046-023-02713-1 doi (DE-627)SPR051646854 (SPR)s13046-023-02713-1-e DE-627 ger DE-627 rakwb eng Rupert, Christofer verfasserin aut Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023. corrected publication 2023 Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. Organoids (dpeaa)DE-He213 Mitochondria (dpeaa)DE-He213 Renal carcinoma (dpeaa)DE-He213 Lysosomes (dpeaa)DE-He213 Purinergic receptors (dpeaa)DE-He213 Drug screening (dpeaa)DE-He213 Dell’ Aversana, Carmela aut Mosca, Laura aut Montanaro, Vittorino aut Arcaniolo, Davide aut De Sio, Marco aut Bilancio, Antonio aut Altucci, Lucia aut Palinski, Wulf aut Pili, Roberto aut de Nigris, Filomena aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-023-02713-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 26 05
allfieldsSound	10.1186/s13046-023-02713-1 doi (DE-627)SPR051646854 (SPR)s13046-023-02713-1-e DE-627 ger DE-627 rakwb eng Rupert, Christofer verfasserin aut Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023. corrected publication 2023 Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. Organoids (dpeaa)DE-He213 Mitochondria (dpeaa)DE-He213 Renal carcinoma (dpeaa)DE-He213 Lysosomes (dpeaa)DE-He213 Purinergic receptors (dpeaa)DE-He213 Drug screening (dpeaa)DE-He213 Dell’ Aversana, Carmela aut Mosca, Laura aut Montanaro, Vittorino aut Arcaniolo, Davide aut De Sio, Marco aut Bilancio, Antonio aut Altucci, Lucia aut Palinski, Wulf aut Pili, Roberto aut de Nigris, Filomena aut Enthalten in Journal of experimental & clinical cancer research Berlin : Springer, 2008 42(2023), 1 vom: 26. Mai (DE-627)568921380 (DE-600)2430698-8 1756-9966 nnns volume:42 year:2023 number:1 day:26 month:05 https://dx.doi.org/10.1186/s13046-023-02713-1 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 42 2023 1 26 05
language	English
source	Enthalten in Journal of experimental & clinical cancer research 42(2023), 1 vom: 26. Mai volume:42 year:2023 number:1 day:26 month:05
sourceStr	Enthalten in Journal of experimental & clinical cancer research 42(2023), 1 vom: 26. Mai volume:42 year:2023 number:1 day:26 month:05
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institution	findex.gbv.de
topic_facet	Organoids Mitochondria Renal carcinoma Lysosomes Purinergic receptors Drug screening
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authorswithroles_txt_mv	Rupert, Christofer @@aut@@ Dell’ Aversana, Carmela @@aut@@ Mosca, Laura @@aut@@ Montanaro, Vittorino @@aut@@ Arcaniolo, Davide @@aut@@ De Sio, Marco @@aut@@ Bilancio, Antonio @@aut@@ Altucci, Lucia @@aut@@ Palinski, Wulf @@aut@@ Pili, Roberto @@aut@@ de Nigris, Filomena @@aut@@
publishDateDaySort_date	2023-05-26T00:00:00Z
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author	Rupert, Christofer
spellingShingle	Rupert, Christofer misc Organoids misc Mitochondria misc Renal carcinoma misc Lysosomes misc Purinergic receptors misc Drug screening Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models
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issn	1756-9966
topic_title	Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models Organoids (dpeaa)DE-He213 Mitochondria (dpeaa)DE-He213 Renal carcinoma (dpeaa)DE-He213 Lysosomes (dpeaa)DE-He213 Purinergic receptors (dpeaa)DE-He213 Drug screening (dpeaa)DE-He213
topic	misc Organoids misc Mitochondria misc Renal carcinoma misc Lysosomes misc Purinergic receptors misc Drug screening
topic_unstemmed	misc Organoids misc Mitochondria misc Renal carcinoma misc Lysosomes misc Purinergic receptors misc Drug screening
topic_browse	misc Organoids misc Mitochondria misc Renal carcinoma misc Lysosomes misc Purinergic receptors misc Drug screening
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title	Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models
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title_full	Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models
author_sort	Rupert, Christofer
journal	Journal of experimental & clinical cancer research
journalStr	Journal of experimental & clinical cancer research
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author_browse	Rupert, Christofer Dell’ Aversana, Carmela Mosca, Laura Montanaro, Vittorino Arcaniolo, Davide De Sio, Marco Bilancio, Antonio Altucci, Lucia Palinski, Wulf Pili, Roberto de Nigris, Filomena
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author-letter	Rupert, Christofer
doi_str_mv	10.1186/s13046-023-02713-1
title_sort	therapeutic targeting of p2x4 receptor and mitochondrial metabolism in clear cell renal carcinoma models
title_auth	Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models
abstract	Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. © The Author(s) 2023. corrected publication 2023
abstractGer	Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. © The Author(s) 2023. corrected publication 2023
abstract_unstemmed	Background Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response. Methods RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry. Results Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model. Conclusion Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy. © The Author(s) 2023. corrected publication 2023
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title_short	Therapeutic targeting of P2X4 receptor and mitochondrial metabolism in clear cell renal carcinoma models
url	https://dx.doi.org/10.1186/s13046-023-02713-1
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author2	Dell’ Aversana, Carmela Mosca, Laura Montanaro, Vittorino Arcaniolo, Davide De Sio, Marco Bilancio, Antonio Altucci, Lucia Palinski, Wulf Pili, Roberto de Nigris, Filomena
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