Nrf2-Dependent Suppression of Azoxymethane/Dextran Sulfate Sodium–Induced Colon Carcinogenesis by the Cinnamon-Derived Dietary Factor Cinnamaldehyde

Abstract

The progressive nature of colorectal cancer (CRC) and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis. Cumulative evidence suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defence, represents a promising molecular target for CRC chemoprevention. Recently, we have identified cinnamon, the ground bark of Cinnamomum aromaticum (cassia cinnamon) and Cinnamomum verum (Ceylon cinnamon), as a rich dietary source of the Nrf2 inducer cinnamaldehyde (CA) eliciting the Nrf2-regulated antioxidant response in human epithelial colon cells, conferring cytoprotection against electrophilic and genotoxic insult. Here, we have explored the molecular mechanism underlying CA-induced Nrf2 activation in colorectal epithelial cells and have examined the chemopreventive potential of CA in a murine CRC model comparing Nrf2+/+ and Nrf2−/− mice. In HCT116 cells, CA caused a Keap1-C151-dependent increase in Nrf2 protein half-life via blockage of ubiquitination with upregulation of cytoprotective Nrf2 target genes and elevation of cellular glutathione. After optimizing colorectal Nrf2 activation and target gene expression by dietary CA-supplementation regimens, we demonstrated that CA suppresses AOM/DSS-induced inflammatory colon carcinogenesis with modulation of molecular markers of colorectal carcinogenesis. Dietary suppression of CRC using CA supplementation was achieved in Nrf2+/+ but not in Nrf2−/− mice confirming the Nrf2-dependence of CA-induced chemopreventive effects. Taken together, our data suggest feasibility of CRC suppression by dietary CA, an FDA-approved food additive derived from the third most consumed spice in the world.

p62 promotes bladder cancer cell growth by activating KEAP1/NRF2‐dependent antioxidative response

“…In addition, NRF2 is the key transcription factor that mediates metabolic reprogramming in cancer cells by increasing glucose uptake and directing it to the pentose phosphate pathway . Many studies have shown that NRF2 also regulates the tumor microenvironment by reducing the expression of proinflammatory cytokines …”

Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis

“…Interestingly, other prior studies have presented experimental evidence that NRF2 activators may protect against radiation-induced dermatitis; however, these studies utilize synthetic triterpenoid NRF2 activators, whereas in our study we repurposed an FDA approved food and cosmetic additive [ 37 , 49 ]. In our own studies, bixin was identified as the result of a screen for diet-derived small molecule NRF2 activators targeting oxidative stress and redox dysregulation in epithelial cells [ 15 , 24 , 26 , 28 , 57 , 58 ]. This current research examines for the first time the efficacy of bixin-based topical activation of cutaneous NRF2 for skin radioprotection and suppression of radiation-induced dermatitis.…”

Protective effects of novel derivatives of vitamin D3 and lumisterol against UVB-induced damage in human keratinocytes involve activation of Nrf2 and P53 defense mechanisms

“…Several synthetic compounds that have the ability to scavenge ROS have been reported to activate Nrf2 expression [15,17,50,86,87], while the silencing of Nrf2 in cells significantly reduced the expression of its target antioxidant genes [15]. The lumisterols derivative, 20(OH)L 3 , has been shown to induce the expression of several genes involved in anti-oxidative responses [45].…”