Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy
Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have sh...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/19/4973 |
| _version_ | 1797516727247962112 |
|---|---|
| author | Yaroslava Karpova Danping Guo Peter Makhov Adam M. Haines Dmitriy A. Markov Vladimir Kolenko Alexei V. Tulin |
| author_facet | Yaroslava Karpova Danping Guo Peter Makhov Adam M. Haines Dmitriy A. Markov Vladimir Kolenko Alexei V. Tulin |
| author_sort | Yaroslava Karpova |
| collection | DOAJ |
| description | Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with extreme accumulation of pADPr caused by the enhanced expression of PARP-1 and decreased PARG levels. The most severe misregulation of pADPr turnover is found in ccRCC specimens from metastatic lesions. Both, classical NAD-like and non-NAD-like PARP-1 inhibitors reduced viability and clonogenic potential of ccRCC cell lines and suppressed growth of ccRCC xenograft tumors. However, classical NAD-like PARP-1 inhibitors affected viability of normal kidney epithelial cells at high concentrations, while novel non-NAD-like PARP-1 inhibitors exhibited activity against malignant cells only. We have also utilized different approaches to reduce the pADPr level in ccRCC cells by stably overexpressing PARG and demonstrated the prominent antitumor effect of this “back-to-normal” intervention. We also generated ccRCC cell lines with stable overexpression of PARG under doxycycline induction. This genetic approach demonstrated significantly affected malignancy of ccRCC cells. Transcriptome analysis linked observed phenotype with changes in gene expression levels for lipid metabolism, interferon signaling, and angiogenesis pathways along with the changes in expression of key cancer-related genes. |
| first_indexed | 2024-03-10T07:04:54Z |
| format | Article |
| id | doaj.art-8aa07d5073ad4a49a4c1d827a8f25c5d |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T07:04:54Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-8aa07d5073ad4a49a4c1d827a8f25c5d2023-11-22T15:55:08ZengMDPI AGCancers2072-66942021-10-011319497310.3390/cancers13194973Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma TherapyYaroslava Karpova0Danping Guo1Peter Makhov2Adam M. Haines3Dmitriy A. Markov4Vladimir Kolenko5Alexei V. Tulin6Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USADepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USAFox Chase Cancer Center, Philadelphia, PA 19111, USADepartment of Cell Biology and Neuroscience, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USADepartment of Cell Biology and Neuroscience, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USAFox Chase Cancer Center, Philadelphia, PA 19111, USADepartment of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USAPoly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with extreme accumulation of pADPr caused by the enhanced expression of PARP-1 and decreased PARG levels. The most severe misregulation of pADPr turnover is found in ccRCC specimens from metastatic lesions. Both, classical NAD-like and non-NAD-like PARP-1 inhibitors reduced viability and clonogenic potential of ccRCC cell lines and suppressed growth of ccRCC xenograft tumors. However, classical NAD-like PARP-1 inhibitors affected viability of normal kidney epithelial cells at high concentrations, while novel non-NAD-like PARP-1 inhibitors exhibited activity against malignant cells only. We have also utilized different approaches to reduce the pADPr level in ccRCC cells by stably overexpressing PARG and demonstrated the prominent antitumor effect of this “back-to-normal” intervention. We also generated ccRCC cell lines with stable overexpression of PARG under doxycycline induction. This genetic approach demonstrated significantly affected malignancy of ccRCC cells. Transcriptome analysis linked observed phenotype with changes in gene expression levels for lipid metabolism, interferon signaling, and angiogenesis pathways along with the changes in expression of key cancer-related genes.https://www.mdpi.com/2072-6694/13/19/4973PARylationPARGPARP-1 inhibitorspoly(ADP-ribose)RCCcancer cell |
| spellingShingle | Yaroslava Karpova Danping Guo Peter Makhov Adam M. Haines Dmitriy A. Markov Vladimir Kolenko Alexei V. Tulin Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy Cancers PARylation PARG PARP-1 inhibitors poly(ADP-ribose) RCC cancer cell |
| title | Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy |
| title_full | Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy |
| title_fullStr | Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy |
| title_full_unstemmed | Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy |
| title_short | Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy |
| title_sort | poly adp ribosylation inhibition a promising approach for clear cell renal cell carcinoma therapy |
| topic | PARylation PARG PARP-1 inhibitors poly(ADP-ribose) RCC cancer cell |
| url | https://www.mdpi.com/2072-6694/13/19/4973 |
| work_keys_str_mv | AT yaroslavakarpova polyadpribosylationinhibitionapromisingapproachforclearcellrenalcellcarcinomatherapy AT danpingguo polyadpribosylationinhibitionapromisingapproachforclearcellrenalcellcarcinomatherapy AT petermakhov polyadpribosylationinhibitionapromisingapproachforclearcellrenalcellcarcinomatherapy AT adammhaines polyadpribosylationinhibitionapromisingapproachforclearcellrenalcellcarcinomatherapy AT dmitriyamarkov polyadpribosylationinhibitionapromisingapproachforclearcellrenalcellcarcinomatherapy AT vladimirkolenko polyadpribosylationinhibitionapromisingapproachforclearcellrenalcellcarcinomatherapy AT alexeivtulin polyadpribosylationinhibitionapromisingapproachforclearcellrenalcellcarcinomatherapy |