p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex
The hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according t...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/3/348 |
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| author | Alessia Garufi Eugenia Giorno Maria Saveria Gilardini Montani Giuseppa Pistritto Alessandra Crispini Mara Cirone Gabriella D’Orazi |
| author_facet | Alessia Garufi Eugenia Giorno Maria Saveria Gilardini Montani Giuseppa Pistritto Alessandra Crispini Mara Cirone Gabriella D’Orazi |
| author_sort | Alessia Garufi |
| collection | DOAJ |
| description | The hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according to tumor stage. The present study aimed at investigating whether the zinc–curcumin Zn(II)–curc compound, which we previously showed to display anticancer effects through multiple mechanisms, could induce NRF2 activation and to explore the underlying molecular mechanisms. Biochemical studies showed that Zn(II)–curc treatment increased the NRF2 protein levels along with its targets, heme oxygenase-1 (HO-1) and p62/SQSTM1, while markedly reduced the levels of Keap1 (Kelch-like ECH-associated protein 1), the NRF2 inhibitor, in the cancer cell lines analyzed. The silencing of either NRF2 or p62/SQSTM1 with specific siRNA demonstrated the crosstalk between the two molecules and that the knockdown of either molecule increased the cancer cell sensitivity to Zn(II)–curc-induced cell death. This suggests that the crosstalk between p62/SQSTM1 and NRF2 could be therapeutically exploited to increase cancer patient response to therapies. |
| first_indexed | 2024-03-09T00:32:01Z |
| format | Article |
| id | doaj.art-fb009911f92f4bc4a825783014bbd80c |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T00:32:01Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-fb009911f92f4bc4a825783014bbd80c2023-12-11T18:27:18ZengMDPI AGBiomolecules2218-273X2021-02-0111334810.3390/biom11030348p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin ComplexAlessia Garufi0Eugenia Giorno1Maria Saveria Gilardini Montani2Giuseppa Pistritto3Alessandra Crispini4Mara Cirone5Gabriella D’Orazi6Unit of Cellular Networks, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyLaboratory MAT_IN LAB, Department of Chemistry and Chemical Technologies, Calabria University, 87036 Rende, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Laboratory Affiliated to Pasteur Institute Italy Foundation Cenci Bolognetti, 00185 Rome, ItalyCentralized Procedures Office, Italian Medicines Agency (AIFA), 00187 Rome, ItalyLaboratory MAT_IN LAB, Department of Chemistry and Chemical Technologies, Calabria University, 87036 Rende, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Laboratory Affiliated to Pasteur Institute Italy Foundation Cenci Bolognetti, 00185 Rome, ItalyUnit of Cellular Networks, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyThe hyperactivation of nuclear factor erythroid 2 p45-related factor 2 (NRF2), frequently found in many tumor types, can be responsible for cancer resistance to therapies and poor patient prognosis. Curcumin has been shown to activate NRF2 that has cytotprotective or protumorigenic roles according to tumor stage. The present study aimed at investigating whether the zinc–curcumin Zn(II)–curc compound, which we previously showed to display anticancer effects through multiple mechanisms, could induce NRF2 activation and to explore the underlying molecular mechanisms. Biochemical studies showed that Zn(II)–curc treatment increased the NRF2 protein levels along with its targets, heme oxygenase-1 (HO-1) and p62/SQSTM1, while markedly reduced the levels of Keap1 (Kelch-like ECH-associated protein 1), the NRF2 inhibitor, in the cancer cell lines analyzed. The silencing of either NRF2 or p62/SQSTM1 with specific siRNA demonstrated the crosstalk between the two molecules and that the knockdown of either molecule increased the cancer cell sensitivity to Zn(II)–curc-induced cell death. This suggests that the crosstalk between p62/SQSTM1 and NRF2 could be therapeutically exploited to increase cancer patient response to therapies.https://www.mdpi.com/2218-273X/11/3/348p62/SQSTM1Keap1NRF2cancer cellsp53zinc compounds |
| spellingShingle | Alessia Garufi Eugenia Giorno Maria Saveria Gilardini Montani Giuseppa Pistritto Alessandra Crispini Mara Cirone Gabriella D’Orazi p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex Biomolecules p62/SQSTM1 Keap1 NRF2 cancer cells p53 zinc compounds |
| title | p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex |
| title_full | p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex |
| title_fullStr | p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex |
| title_full_unstemmed | p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex |
| title_short | p62/SQSTM1/Keap1/NRF2 Axis Reduces Cancer Cells Death-Sensitivity in Response to Zn(II)–Curcumin Complex |
| title_sort | p62 sqstm1 keap1 nrf2 axis reduces cancer cells death sensitivity in response to zn ii curcumin complex |
| topic | p62/SQSTM1 Keap1 NRF2 cancer cells p53 zinc compounds |
| url | https://www.mdpi.com/2218-273X/11/3/348 |
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