Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells
Non–small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558616301129 |
| _version_ | 1828185243061846016 |
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| author | Jair Bar Mohamed S. Hasim Tabassom Baghai Nima Niknejad Theodore J. Perkins David J. Stewart Harmanjatinder S. Sekhon Patrick J. Villeneuve Jim Dimitroulakos |
| author_facet | Jair Bar Mohamed S. Hasim Tabassom Baghai Nima Niknejad Theodore J. Perkins David J. Stewart Harmanjatinder S. Sekhon Patrick J. Villeneuve Jim Dimitroulakos |
| author_sort | Jair Bar |
| collection | DOAJ |
| description | Non–small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6). Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC. |
| first_indexed | 2024-04-12T07:01:49Z |
| format | Article |
| id | doaj.art-62c40392758141428b661fe1a30fdc89 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-04-12T07:01:49Z |
| publishDate | 2016-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-62c40392758141428b661fe1a30fdc892022-12-22T03:43:00ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022016-09-0118952553510.1016/j.neo.2016.07.004Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma CellsJair Bar0Mohamed S. Hasim1Tabassom Baghai2Nima Niknejad3Theodore J. Perkins4David J. Stewart5Harmanjatinder S. Sekhon6Patrick J. Villeneuve7Jim Dimitroulakos8Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaCentre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaCentre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaCentre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaRegenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaDepartment of Medical Oncology, the Ottawa Hospital, Ottawa, Ontario, CanadaDepartment of Anatomical Pathology, the Ottawa Hospital, Ottawa, Ontario, CanadaCentre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaCentre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, CanadaNon–small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6). Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC.http://www.sciencedirect.com/science/article/pii/S1476558616301129 |
| spellingShingle | Jair Bar Mohamed S. Hasim Tabassom Baghai Nima Niknejad Theodore J. Perkins David J. Stewart Harmanjatinder S. Sekhon Patrick J. Villeneuve Jim Dimitroulakos Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells Neoplasia: An International Journal for Oncology Research |
| title | Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells |
| title_full | Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells |
| title_fullStr | Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells |
| title_full_unstemmed | Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells |
| title_short | Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non–Small Cell Lung Carcinoma Cells |
| title_sort | induction of activating transcription factor 3 is associated with cisplatin responsiveness in non small cell lung carcinoma cells |
| url | http://www.sciencedirect.com/science/article/pii/S1476558616301129 |
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