Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells
Abstract Background Oxaliplatin belongs to the platinum-based drug family and has shown promise in treating cancer by binding to DNA to induce cytotoxicity. However, individual patients show diverse therapeutic responses toward oxaliplatin due to yet-unknown underlying mechanisms. We recently establ...
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| Format: | Article |
| Language: | English |
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BMC
2018-07-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | http://link.springer.com/article/10.1186/s13046-018-0837-9 |
| _version_ | 1818887264635191296 |
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| author | Huei-Yu Chen Atikul Islam Tien-Ming Yuan Shi-Wen Chen Pei-Fen Liu Pin Ju Chueh |
| author_facet | Huei-Yu Chen Atikul Islam Tien-Ming Yuan Shi-Wen Chen Pei-Fen Liu Pin Ju Chueh |
| author_sort | Huei-Yu Chen |
| collection | DOAJ |
| description | Abstract Background Oxaliplatin belongs to the platinum-based drug family and has shown promise in treating cancer by binding to DNA to induce cytotoxicity. However, individual patients show diverse therapeutic responses toward oxaliplatin due to yet-unknown underlying mechanisms. We recently established that oxaliplatin also exert its anti-cancer activity in gastric cancer cell lines by targeting tumor-associated NADH oxidase (tNOX), attenuate NAD+ generation and reduce NAD+-dependent sirtuin 1 (SIRT1) deacetylase activity, which in turn enhances p53 acetylation and apoptosis. Methods In this study, differential cellular outcomes in response to oxaliplatin exposure of p53-wild-type versus p53-null HCT116 human colon cancer cells were examined. Cell growth profile was determined by cell impedance measurements and apoptosis was analyzed by flow cytometry. The engagement between oxaliplatin and tNOX protein was studied by cellular thermal shift assay. Furthermore, western blot analysis revealed that p53 was important in regulating tNOX expression in these cell lines. Results In p53-wild-type cells, we found that oxaliplatin inhibited cell growth by inducing apoptosis and concurrently down-regulating tNOX at both the transcriptional and translational levels. In p53-null cells, in contrast, oxaliplatin moderately up-regulated tNOX expression and yielded no apoptosis and much less cytotoxicity. Further experiments revealed that in p53-wild-type cells, oxaliplatin enhanced ROS generation and p53 transcriptional activation, leading to down-regulation of the transcriptional factor, POU3F2, which enhances the expression of tNOX. Moreover, the addition of a ROS scavenger reversed the p53 activation, POU3F2 down-regulation, and apoptosis induced by oxaliplatin in p53-wild-type cells. In the p53-null line, on the other hand, oxaliplatin treatment triggered less ROS generation and no p53 protein, such that POU3F2 and tNOX were not down-regulated and oxaliplatin-mediated cytotoxicity was attenuated. Conclusion Our results show that oxaliplatin mediates differential cellular responses in colon cancer cells depending on their p53 status, and demonstrate that the ROS-p53 axis is important for regulating POU3F2 and its downstream target, tNOX. Notably, the depletion of tNOX sensitizes p53-null cells to both spontaneous and oxaliplatin-induced apoptosis. Our work thus clearly shows a scenario in which targeting of tNOX may be a potential strategy for cancer therapy in a p53-inactivated system. |
| first_indexed | 2024-12-19T16:34:28Z |
| format | Article |
| id | doaj.art-f4614ebe1f7f4276b2025fde44d3805a |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-19T16:34:28Z |
| publishDate | 2018-07-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-f4614ebe1f7f4276b2025fde44d3805a2022-12-21T20:14:02ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662018-07-0137111410.1186/s13046-018-0837-9Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cellsHuei-Yu Chen0Atikul Islam1Tien-Ming Yuan2Shi-Wen Chen3Pei-Fen Liu4Pin Ju Chueh5Institute of Biomedical Sciences, National Chung Hsing UniversityInstitute of Biomedical Sciences, National Chung Hsing UniversityDepartment of Surgery, Feng-Yuan Hospital, Ministry of Health and WelfareDepartment of Surgery, Feng-Yuan Hospital, Ministry of Health and WelfareDDepartment of Food Science and Biotechnology, National Chung Hsing UniversityInstitute of Biomedical Sciences, National Chung Hsing UniversityAbstract Background Oxaliplatin belongs to the platinum-based drug family and has shown promise in treating cancer by binding to DNA to induce cytotoxicity. However, individual patients show diverse therapeutic responses toward oxaliplatin due to yet-unknown underlying mechanisms. We recently established that oxaliplatin also exert its anti-cancer activity in gastric cancer cell lines by targeting tumor-associated NADH oxidase (tNOX), attenuate NAD+ generation and reduce NAD+-dependent sirtuin 1 (SIRT1) deacetylase activity, which in turn enhances p53 acetylation and apoptosis. Methods In this study, differential cellular outcomes in response to oxaliplatin exposure of p53-wild-type versus p53-null HCT116 human colon cancer cells were examined. Cell growth profile was determined by cell impedance measurements and apoptosis was analyzed by flow cytometry. The engagement between oxaliplatin and tNOX protein was studied by cellular thermal shift assay. Furthermore, western blot analysis revealed that p53 was important in regulating tNOX expression in these cell lines. Results In p53-wild-type cells, we found that oxaliplatin inhibited cell growth by inducing apoptosis and concurrently down-regulating tNOX at both the transcriptional and translational levels. In p53-null cells, in contrast, oxaliplatin moderately up-regulated tNOX expression and yielded no apoptosis and much less cytotoxicity. Further experiments revealed that in p53-wild-type cells, oxaliplatin enhanced ROS generation and p53 transcriptional activation, leading to down-regulation of the transcriptional factor, POU3F2, which enhances the expression of tNOX. Moreover, the addition of a ROS scavenger reversed the p53 activation, POU3F2 down-regulation, and apoptosis induced by oxaliplatin in p53-wild-type cells. In the p53-null line, on the other hand, oxaliplatin treatment triggered less ROS generation and no p53 protein, such that POU3F2 and tNOX were not down-regulated and oxaliplatin-mediated cytotoxicity was attenuated. Conclusion Our results show that oxaliplatin mediates differential cellular responses in colon cancer cells depending on their p53 status, and demonstrate that the ROS-p53 axis is important for regulating POU3F2 and its downstream target, tNOX. Notably, the depletion of tNOX sensitizes p53-null cells to both spontaneous and oxaliplatin-induced apoptosis. Our work thus clearly shows a scenario in which targeting of tNOX may be a potential strategy for cancer therapy in a p53-inactivated system.http://link.springer.com/article/10.1186/s13046-018-0837-9ApoptosisOxaliplatinp53Tumor-associated NADH oxidase (tNOX or ENOX2)Sirtuin 1 (SIRT1)ROS |
| spellingShingle | Huei-Yu Chen Atikul Islam Tien-Ming Yuan Shi-Wen Chen Pei-Fen Liu Pin Ju Chueh Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells Journal of Experimental & Clinical Cancer Research Apoptosis Oxaliplatin p53 Tumor-associated NADH oxidase (tNOX or ENOX2) Sirtuin 1 (SIRT1) ROS |
| title | Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells |
| title_full | Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells |
| title_fullStr | Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells |
| title_full_unstemmed | Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells |
| title_short | Regulation of tNOX expression through the ROS-p53-POU3F2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells |
| title_sort | regulation of tnox expression through the ros p53 pou3f2 axis contributes to cellular responses against oxaliplatin in human colon cancer cells |
| topic | Apoptosis Oxaliplatin p53 Tumor-associated NADH oxidase (tNOX or ENOX2) Sirtuin 1 (SIRT1) ROS |
| url | http://link.springer.com/article/10.1186/s13046-018-0837-9 |
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