Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment
Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase sub...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-08-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/16/4200 |
| _version_ | 1797524372990197760 |
|---|---|
| author | Christina Bothou Ashish Sharma Adrian Oo Baek Kim Pal Perge Peter Igaz Cristina L. Ronchi Igor Shapiro Constanze Hantel |
| author_facet | Christina Bothou Ashish Sharma Adrian Oo Baek Kim Pal Perge Peter Igaz Cristina L. Ronchi Igor Shapiro Constanze Hantel |
| author_sort | Christina Bothou |
| collection | DOAJ |
| description | Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC. |
| first_indexed | 2024-03-10T08:56:26Z |
| format | Article |
| id | doaj.art-510c645476e040d28ca02641b4cd3ba4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T08:56:26Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-510c645476e040d28ca02641b4cd3ba42023-11-22T07:05:15ZengMDPI AGCancers2072-66942021-08-011316420010.3390/cancers13164200Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma TreatmentChristina Bothou0Ashish Sharma1Adrian Oo2Baek Kim3Pal Perge4Peter Igaz5Cristina L. Ronchi6Igor Shapiro7Constanze Hantel8Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), CH-8091 Zurich, SwitzerlandDepartment of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), CH-8091 Zurich, SwitzerlandDepartment of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USADepartment of Pediatrics, School of Medicine, Emory University, Atlanta, GA 30322, USADepartment of Endocrinology, Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, H-1083 Budapest, HungaryDepartment of Endocrinology, Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, H-1083 Budapest, HungaryDivision of Endocrinology and Diabetes, Department of Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, GermanyDepartment of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), CH-8091 Zurich, SwitzerlandDepartment of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), CH-8091 Zurich, SwitzerlandCurrent systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.https://www.mdpi.com/2072-6694/13/16/4200adrenocortical carcinomaadrenocortical cell lineRRM2RNRCOH29 |
| spellingShingle | Christina Bothou Ashish Sharma Adrian Oo Baek Kim Pal Perge Peter Igaz Cristina L. Ronchi Igor Shapiro Constanze Hantel Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment Cancers adrenocortical carcinoma adrenocortical cell line RRM2 RNR COH29 |
| title | Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment |
| title_full | Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment |
| title_fullStr | Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment |
| title_full_unstemmed | Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment |
| title_short | Novel Insights into the Molecular Regulation of Ribonucleotide Reductase in Adrenocortical Carcinoma Treatment |
| title_sort | novel insights into the molecular regulation of ribonucleotide reductase in adrenocortical carcinoma treatment |
| topic | adrenocortical carcinoma adrenocortical cell line RRM2 RNR COH29 |
| url | https://www.mdpi.com/2072-6694/13/16/4200 |
| work_keys_str_mv | AT christinabothou novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment AT ashishsharma novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment AT adrianoo novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment AT baekkim novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment AT palperge novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment AT peterigaz novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment AT cristinalronchi novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment AT igorshapiro novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment AT constanzehantel novelinsightsintothemolecularregulationofribonucleotidereductaseinadrenocorticalcarcinomatreatment |