Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma
Constitutive activation of nuclear factor erythroid 2-related factor 2 (NRF2) is pivotal in bestowing therapy resistance in cancer cells. Several phytochemicals have been reported with the potential of modulating NRF2. Therefore, it was hypothesized that NRF2-deregulated chemoresistance in lung aden...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1176819/full |
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| author | Suchisnigdha Datta Anupam Bishayee Dona Sinha |
| author_facet | Suchisnigdha Datta Anupam Bishayee Dona Sinha |
| author_sort | Suchisnigdha Datta |
| collection | DOAJ |
| description | Constitutive activation of nuclear factor erythroid 2-related factor 2 (NRF2) is pivotal in bestowing therapy resistance in cancer cells. Several phytochemicals have been reported with the potential of modulating NRF2. Therefore, it was hypothesized that NRF2-deregulated chemoresistance in lung adenocarcinoma (LUAD) may be counteracted by theaflavin-rich black tea (BT). A non-responsive LUAD cell line, A549, was the best sensitized towards cisplatin upon pre-treatment with BT. BT-mediated NRF2 reorientation was observed to be dependent on concentration and duration of treatment as well as on the mutational profile of NRF2 in A549 cells. Transient exposure of low-concentration BT hormetically downregulated NRF2, its downstream antioxidants, and drug transporter. BT also influenced the Kelch-like ECH-associated protein (KEAP1)-dependent cullin 3 (Cul3) and KEAP-1-independent signaling through epidermal growth factor receptor (EGFR) - rat sarcoma virus (RAS) - rapidly accelerated fibrosarcoma (RAF) - extracellular signal-regulated kinase 1/2 (ERK) - matrix metalloproteinase (MMP)-2 and MMP-9. The realignment of NRF2 in KEAP1-suppressed A549 cells enhanced the chemotherapeutic outcome. But a higher concentration of the same BT surprisingly upregulated NRF2 and its transcriptional targets with a subsequent decrease in the NRF2-regulatory machinery in NCI-H23 cells (a KEAP1-overexpressed LUAD cell line), ultimately resulting in a better anticancer response. The BT-mediated bidirectional NRF2 modulation was reconfirmed upon comparison with the action of a pharmacological NRF2 inhibitor, ML-385, in A549 and a known NRF2 activator, tertiary-butylhydroquinone, in NCI-H23 respectively. BT-mediated regulation of NRF2-KEAP1 and their upstream networks (EGFR/RAS/RAF/ERK) sufficed as a better anticancer agent than synthetic NRF2 modulators. Therefore, BT may be indicated as a potent multi-modal small molecule for increasing drug responsiveness in LUAD cells by maintaining NRF2/KEAP1 axis at an optimum level. |
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| id | doaj.art-f451997a01db44168f15d1ee5f6a0577 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T09:47:04Z |
| publishDate | 2023-05-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-f451997a01db44168f15d1ee5f6a05772023-05-25T04:19:53ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-05-011410.3389/fphar.2023.11768191176819Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinomaSuchisnigdha Datta0Anupam Bishayee1Dona Sinha2Department of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, Kolkata, West Bengal, IndiaCollege of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, United StatesDepartment of Receptor Biology and Tumor Metastasis, Chittaranjan National Cancer Institute, Kolkata, West Bengal, IndiaConstitutive activation of nuclear factor erythroid 2-related factor 2 (NRF2) is pivotal in bestowing therapy resistance in cancer cells. Several phytochemicals have been reported with the potential of modulating NRF2. Therefore, it was hypothesized that NRF2-deregulated chemoresistance in lung adenocarcinoma (LUAD) may be counteracted by theaflavin-rich black tea (BT). A non-responsive LUAD cell line, A549, was the best sensitized towards cisplatin upon pre-treatment with BT. BT-mediated NRF2 reorientation was observed to be dependent on concentration and duration of treatment as well as on the mutational profile of NRF2 in A549 cells. Transient exposure of low-concentration BT hormetically downregulated NRF2, its downstream antioxidants, and drug transporter. BT also influenced the Kelch-like ECH-associated protein (KEAP1)-dependent cullin 3 (Cul3) and KEAP-1-independent signaling through epidermal growth factor receptor (EGFR) - rat sarcoma virus (RAS) - rapidly accelerated fibrosarcoma (RAF) - extracellular signal-regulated kinase 1/2 (ERK) - matrix metalloproteinase (MMP)-2 and MMP-9. The realignment of NRF2 in KEAP1-suppressed A549 cells enhanced the chemotherapeutic outcome. But a higher concentration of the same BT surprisingly upregulated NRF2 and its transcriptional targets with a subsequent decrease in the NRF2-regulatory machinery in NCI-H23 cells (a KEAP1-overexpressed LUAD cell line), ultimately resulting in a better anticancer response. The BT-mediated bidirectional NRF2 modulation was reconfirmed upon comparison with the action of a pharmacological NRF2 inhibitor, ML-385, in A549 and a known NRF2 activator, tertiary-butylhydroquinone, in NCI-H23 respectively. BT-mediated regulation of NRF2-KEAP1 and their upstream networks (EGFR/RAS/RAF/ERK) sufficed as a better anticancer agent than synthetic NRF2 modulators. Therefore, BT may be indicated as a potent multi-modal small molecule for increasing drug responsiveness in LUAD cells by maintaining NRF2/KEAP1 axis at an optimum level.https://www.frontiersin.org/articles/10.3389/fphar.2023.1176819/fullblack tealung adenocarcinomachemoresistanceNRF2KEAP1redox signaling |
| spellingShingle | Suchisnigdha Datta Anupam Bishayee Dona Sinha Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma Frontiers in Pharmacology black tea lung adenocarcinoma chemoresistance NRF2 KEAP1 redox signaling |
| title | Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma |
| title_full | Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma |
| title_fullStr | Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma |
| title_full_unstemmed | Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma |
| title_short | Black tea bioactive phytoconstituents realign NRF2 for anticancer activity in lung adenocarcinoma |
| title_sort | black tea bioactive phytoconstituents realign nrf2 for anticancer activity in lung adenocarcinoma |
| topic | black tea lung adenocarcinoma chemoresistance NRF2 KEAP1 redox signaling |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1176819/full |
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