Abstract
BackgroundA. oxyphylla extract is known to possess a wide range of pharmacological activites. However, the molecular mechanism of A. oxyphylla and its bioactive compound nootkatone in colorectal cancer is unknown.MethodsOur study aims to examine the role of A. oxyphylla and its bioactive compound nootkatone, in tumor suppression using several in vitro assays.ResultsBoth A. oxyphylla extract and nootkatone exhibited antiproliferative activity in colorectal cancer cells. A. oxyphylla displayed antioxidant activity in colorectal cancer cells, likely mediated via induction of HO-1. Furthermore, expression of pro-apoptotic protein NAG-1 and cell proliferative protein cyclin D1 were increased and decreased respectively in the presence of A. oxyphylla. When examined for anticancer activity, nootkatone treatment resulted in the reduction of colony and spheroid formation. Correspondingly, nootkatone also led to increased NAG-1 expression and decreased cyclin D1 expression. The mechanism by which nootkatone suppresses cyclin D1 involves protein level regulation, whereas nootkatone increases NAG-1 expression at the transcriptional level. In addition to having PPARγ binding activity, nootkatone also increases EGR-1 expression which ultimately results in enhanced NAG-1 promoter activity.ConclusionIn summary, our findings suggest that nootkatone is an anti-tumorigenic compound harboring antiproliferative and pro-apoptotic activity.
Highlights
A. oxyphylla extract is known to possess a wide range of pharmacological activites
We identified the biological activity of A. oxyphylla and its major compound nootkatone as an inducer of the pro-apoptotic protein Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) and a suppressor of cyclin D1, thereby inhibiting cell proliferation in colon cancer cells
Our results indicated that Early Growth Response 1 (EGR-1) plays a pivotal role in nootkatone-induced NAG-1 expression, while the proteosomal degradation pathway contributes to nootkatone-mediated cyclin D1 downregulation
Summary
A. oxyphylla extract is known to possess a wide range of pharmacological activites. The molecular mechanism of A. oxyphylla and its bioactive compound nootkatone in colorectal cancer is unknown. Nootkatone has been identified as the main fragrant component of grapefruit with a wide range of beneficial effects including anti-inflammation activities [7], AMPK activation [8] and neuroprotective effects [9]. Other bioactive compounds in A. oxyphylla, Yoo et al BMC Cancer (2020) 20:881 yakuchinone A [10] and yakuchinone B [11], are known to have several biological activities including anti-cancer activity. The molecular target of nootkatone and other bioactive compounds in cancer or in cell proliferation is unknown
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