PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
Ameliorative Inhibition of SIRT6 by Imidazole Derivative Triggers Oxidative Stress-Mediated Apoptosis Associated with Nrf2/Keap1 Signaling in NSCLC Cell Lines
Dindi, U.M.R.; Al-Ghamdi, S.; Alrudian, N.; Salman, B.D.; Abuderman, A.A.; Mohammad, S.; Ramesh, T.; Vilwanathan, R. Ameliorative Inhibition of SIRT6 by Imidazole Derivative Triggers Oxidative Stress-Mediated Apoptosis Associated with Nrf2/Keap1 Signaling in NSCLC Cell Lines. Preprints2023, 2023080482. https://doi.org/10.20944/preprints202308.0482.v1
APA Style
Dindi, U.M.R., Al-Ghamdi, S., Alrudian, N., Salman, B.D., Abuderman, A.A., Mohammad, S., Ramesh, T., & Vilwanathan, R. (2023). Ameliorative Inhibition of SIRT6 by Imidazole Derivative Triggers Oxidative Stress-Mediated Apoptosis Associated with Nrf2/Keap1 Signaling in NSCLC Cell Lines. Preprints. https://doi.org/10.20944/preprints202308.0482.v1
Chicago/Turabian Style
Dindi, U.M.R., Thiyagarajan Ramesh and Ravikumar Vilwanathan. 2023 "Ameliorative Inhibition of SIRT6 by Imidazole Derivative Triggers Oxidative Stress-Mediated Apoptosis Associated with Nrf2/Keap1 Signaling in NSCLC Cell Lines" Preprints. https://doi.org/10.20944/preprints202308.0482.v1
Abstract
The nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, also called Nfe2l2)/Kelchlike ECH-associated protein 1 (Keap1) signaling is the major regulator of redox homeostasis. The imbalance of redox homeostasis causes oxidative stress. Keap1 is the one that regulates Nrf2 by binding to Nrf2. Nrf2/Keap1 signaling is reported to be involved in cancer cell growth and survival. The high level of Nrf2 in cancers is associated with poor prognosis, resistance to therapeutics and rapid proliferation framing Nrf2 as an interesting target in cancer biology. Sirtuins (SIRT1-7) are class III histone deacetylases with NAD+-dependent deacetylase activity. High levels of SIRT6 are contributing to cancer progression in many types of human tumors, and its overexpression has been reported to involve positive modulation of the Nrf2/Keap1 pathway, suggesting SIRT6 is a key regulator of this Nrf2/Keap1 Signaling. The natural or synthetic compound that inhibits key regulators of Nrf2 signaling becomes an attractive target. In the present study, we investigated the pharmacological effect of Ethyl (5-(4-Chlorophenyl)-2-methyl-1H-imidazol-4-yl) - acetate an imidazole derivative on Nrf2/Keap1 in A549 and NIC-H460 cell lines. Imidazole derivative inhibited the SIRT6 expression at gene and protein levels. The gene and protein expression of Nrf2 and Keap1 were modulated during SIRT6 inhibition. The level of anti-oxidant enzymes such as GSH, GPx, Catalase, and % ROS scavenging activity were depleted upon SIRT6 inhibition. Further, morphological studies support ROS generation, mitochondrial damage, nuclear damage, and apoptosis. The molecular examination of apoptosis by gene and protein expression of apoptotic factors confirms apoptotic cell death. Our results suggest that the Imidazole derivative affects Nrf2/Keap1 signaling by targeting SIRT6 might be a new promising approach to cancer treatment opportunity for disrupting Nrf2/Keap1 signaling in lung cancer.
Keywords
Epigenetics; SIRT6; HDAC; HDACi; KEAP1; NRF2
Subject
Biology and Life Sciences, Life Sciences
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
,
,
,
,
,
*
,
*
