Abstract
Colorectal cancer (CRC) is a common malignant gastrointestinal tumor with high mortality worldwide. Drug resistance and cytotoxicity to normal cells are the main causes of chemotherapeutic treatment failure in CRC. Therefore, extracting the bioactive compounds from natural products with anti-carcinogenic activity and minimal side-effects is a promising strategy against CRC. The present study aims to evaluate the anti-carcinogenic properties of avenanthramides (AVNs) extracted from oats bran and clarify the underlying molecular mechanisms. We demonstrated that AVNs treatment suppressed mitochondrial bioenergetic generation, resulting in mitochondrial swelling and increased reactive oxygen species (ROS) production. Further study indicated that AVNs treatment significantly reduced DDX3 expression, an oncogenic RNA helicase highly expressed in human CRC tissues. DDX3 overexpression reversed the ROS-mediated CRC apoptosis induced by AVNs. Of note, we identified Avenanthramide A (AVN A) as the effective ingredient in AVNs extracts. AVN A blocked the ATPase activity of DDX3 and induced its degradation by directly binding to the Arg287 and Arg294 residues in DDX3. In conclusion, these innovative findings highlight that AVNs extracts, in particular its bioactive compound AVN A may crack the current hurdles in the way of CRC treatment.
Highlights
Colorectal cancer (CRC) is one of the most common tumors of the digestive tract; with high morbidity and mortality rates worldwide[1]
We further identified Avenanthramide A (AVN A) as the main active compound in AVNs extract, which binds to DDX3 protein at Arg[287] and Arg[294] residues to inhibit its ATP hydrolysis activity and protein stability
Identification was determined on the basis of protonated molecular ions [M + H]+, according to Hitayezu et al, signals with m/z values of 300, 330 and 316 were considered as avenanthramide A (AVN A), avenanthramide B (AVN B), and avenanthramide C (AVN C), respectively (Fig. 1b)[13]
Summary
Colorectal cancer (CRC) is one of the most common tumors of the digestive tract; with high morbidity and mortality rates worldwide[1]. Due to obtrusive drug resistance and potent side effects, the outcomes of current chemotherapy drugs are not so desirable[2]. Exploring the bioactive anti-cancer compounds derived from natural products with low toxicity and minimal side effects has emerged as a hot topic in cancer biology. Oats (Avena sativa L.) is a wholegrain cereal and an important edible crop, which contains several bioactive ingredients[3]. The imbalance between free radical generation and intracellular scavenging activity give rise to the production of excess level of reactive oxygen species (ROS). Mitochondrial ROS generation is largely coupled to mitochondrial respiration.
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