Increased expression of autophagy and Nrf2-dependent signaling pathway genes by new monophenolic antioxidants depends on their structure
Under certain conditions, both activators and inhibitors of Nrf2-dependent signaling and autophagy can serve as potential agents for the prevention, treatment, and maintenance therapy of cancer, as well as overcoming chemoresistance. We are developing a panel of structurally related synthetic monoph...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | Russian |
| Published: |
Russian Academy of Sciences, Siberian Branch Publishing House
2021-06-01
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| Series: | Сибирский научный медицинский журнал |
| Subjects: | |
| Online Access: | https://sibmed.elpub.ru/jour/article/view/598 |
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| author | S. E. Khrapov P. M. Kozhin M. V. Khrapova A. E. Serykh L. P. Romakh V. S. Pavlov A. V. Chechushkov S. V. Kholshin N. K. Zenkov E. B. Menshchikova |
| author_facet | S. E. Khrapov P. M. Kozhin M. V. Khrapova A. E. Serykh L. P. Romakh V. S. Pavlov A. V. Chechushkov S. V. Kholshin N. K. Zenkov E. B. Menshchikova |
| author_sort | S. E. Khrapov |
| collection | DOAJ |
| description | Under certain conditions, both activators and inhibitors of Nrf2-dependent signaling and autophagy can serve as potential agents for the prevention, treatment, and maintenance therapy of cancer, as well as overcoming chemoresistance. We are developing a panel of structurally related synthetic monophenolic compounds, in addition to a direct antioxidant effect, having the ability to affect intracellular signaling pathways and processes, including the above mentioned. Aim of the study was to investigate the relationship between its structure and the ability to influence the expression of autophagy and Nrf2 pathway genes.Material and methods. Five original hydrophilic phenolic structurally related compounds were synthesized; the prototypical inductor of the Keap1/Nrf2/ARE system, monosubstituted phenol tert-butylhydro-quinone (tBHQ), served as a reference substance. We used cultures of murine Lewis lung carcinoma (LLC) and human breast adenocarcinoma MCF-7 cells, with the test compounds at a concentration of 20 gM cells were incubated for 24 hours. Changes in mRNA expression of Nrf2, Nqo1, LC3b, and Sqstm1 genes encoding Nrf2, NAD(P)H:quinone oxidoreductase-1, LC3B, p62/sequestosome-1, respectively, were determined by TaqMan real-time PCR.Results and discussion. Structurally related synthetic monophenols effectively induced the Keap1/Nrf2/ARE system in LLC and MCF-7 cells, increasing the expression of the Nrf2-driven Nqo1 gene, and ambiguously affected the transcription of genes of proteins mediating autophagy: the content of mRNA of the LC3B protein did not change, while the expression of mRNA of the p62 protein, which affects the operation of both systems (processes), is increased only by the action of ortho-monosubstituted phenol with an «active» sulfur atom in the para-propyl substituent TS-13 and its structural analogue TS-12 with a para-substituent shortened by one methylene. It can be assumed that the observed effect either indicates the ability of TS-13 and TS-12 both to induce the Keap1/Nrf2/ARE system and to stimulate autophagy, or reflects a compound-mediated mutually reinforcing cross-activation of these processes. |
| first_indexed | 2024-03-08T14:34:20Z |
| format | Article |
| id | doaj.art-b5fda36ed7084758af04b032e864aa8b |
| institution | Directory Open Access Journal |
| issn | 2410-2512 2410-2520 |
| language | Russian |
| last_indexed | 2024-04-25T01:50:10Z |
| publishDate | 2021-06-01 |
| publisher | Russian Academy of Sciences, Siberian Branch Publishing House |
| record_format | Article |
| series | Сибирский научный медицинский журнал |
| spelling | doaj.art-b5fda36ed7084758af04b032e864aa8b2024-03-07T18:49:59ZrusRussian Academy of Sciences, Siberian Branch Publishing HouseСибирский научный медицинский журнал2410-25122410-25202021-06-01413253110.18699/SSMJ20210303347Increased expression of autophagy and Nrf2-dependent signaling pathway genes by new monophenolic antioxidants depends on their structureS. E. Khrapov0P. M. Kozhin1M. V. Khrapova2A. E. Serykh3L. P. Romakh4V. S. Pavlov5A. V. Chechushkov6S. V. Kholshin7N. K. Zenkov8E. B. Menshchikova9Federal Research Center of Fundamental and Translational MedicineFederal Research Center of Fundamental and Translational MedicineFederal Research Center of Fundamental and Translational MedicineFederal Research Center of Fundamental and Translational MedicineFederal Research Center of Fundamental and Translational MedicineFederal Research Center of Fundamental and Translational MedicineFederal Research Center of Fundamental and Translational MedicineNovosibirsk State Pedagogical UniversityFederal Research Center of Fundamental and Translational MedicineFederal Research Center of Fundamental and Translational MedicineUnder certain conditions, both activators and inhibitors of Nrf2-dependent signaling and autophagy can serve as potential agents for the prevention, treatment, and maintenance therapy of cancer, as well as overcoming chemoresistance. We are developing a panel of structurally related synthetic monophenolic compounds, in addition to a direct antioxidant effect, having the ability to affect intracellular signaling pathways and processes, including the above mentioned. Aim of the study was to investigate the relationship between its structure and the ability to influence the expression of autophagy and Nrf2 pathway genes.Material and methods. Five original hydrophilic phenolic structurally related compounds were synthesized; the prototypical inductor of the Keap1/Nrf2/ARE system, monosubstituted phenol tert-butylhydro-quinone (tBHQ), served as a reference substance. We used cultures of murine Lewis lung carcinoma (LLC) and human breast adenocarcinoma MCF-7 cells, with the test compounds at a concentration of 20 gM cells were incubated for 24 hours. Changes in mRNA expression of Nrf2, Nqo1, LC3b, and Sqstm1 genes encoding Nrf2, NAD(P)H:quinone oxidoreductase-1, LC3B, p62/sequestosome-1, respectively, were determined by TaqMan real-time PCR.Results and discussion. Structurally related synthetic monophenols effectively induced the Keap1/Nrf2/ARE system in LLC and MCF-7 cells, increasing the expression of the Nrf2-driven Nqo1 gene, and ambiguously affected the transcription of genes of proteins mediating autophagy: the content of mRNA of the LC3B protein did not change, while the expression of mRNA of the p62 protein, which affects the operation of both systems (processes), is increased only by the action of ortho-monosubstituted phenol with an «active» sulfur atom in the para-propyl substituent TS-13 and its structural analogue TS-12 with a para-substituent shortened by one methylene. It can be assumed that the observed effect either indicates the ability of TS-13 and TS-12 both to induce the Keap1/Nrf2/ARE system and to stimulate autophagy, or reflects a compound-mediated mutually reinforcing cross-activation of these processes.https://sibmed.elpub.ru/jour/article/view/598antioxidantskeap1/nrf2/are signaling systemnad(p)h:quinone oxidoreductase-1nrf2nqo1lc3bsqstm1 |
| spellingShingle | S. E. Khrapov P. M. Kozhin M. V. Khrapova A. E. Serykh L. P. Romakh V. S. Pavlov A. V. Chechushkov S. V. Kholshin N. K. Zenkov E. B. Menshchikova Increased expression of autophagy and Nrf2-dependent signaling pathway genes by new monophenolic antioxidants depends on their structure Сибирский научный медицинский журнал antioxidants keap1/nrf2/are signaling system nad(p)h:quinone oxidoreductase-1 nrf2 nqo1 lc3b sqstm1 |
| title | Increased expression of autophagy and Nrf2-dependent signaling pathway genes by new monophenolic antioxidants depends on their structure |
| title_full | Increased expression of autophagy and Nrf2-dependent signaling pathway genes by new monophenolic antioxidants depends on their structure |
| title_fullStr | Increased expression of autophagy and Nrf2-dependent signaling pathway genes by new monophenolic antioxidants depends on their structure |
| title_full_unstemmed | Increased expression of autophagy and Nrf2-dependent signaling pathway genes by new monophenolic antioxidants depends on their structure |
| title_short | Increased expression of autophagy and Nrf2-dependent signaling pathway genes by new monophenolic antioxidants depends on their structure |
| title_sort | increased expression of autophagy and nrf2 dependent signaling pathway genes by new monophenolic antioxidants depends on their structure |
| topic | antioxidants keap1/nrf2/are signaling system nad(p)h:quinone oxidoreductase-1 nrf2 nqo1 lc3b sqstm1 |
| url | https://sibmed.elpub.ru/jour/article/view/598 |
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