Abstract
Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.
Highlights
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide in 2020 with an estimated 1.8 million new cases [1]
In head and neck squamous cell carcinomas, δVB caused a severe inhibition of cell proliferation together with induction of apoptosis and cell cycle arrest in the G2/M phase [6]. δVB determined an accumulation of mitochondrial reactive oxygen species (ROS) and influenced the expression and activity of SIRT1
This study aimed to deepen the mechanism of δVB-induced apoptosis in SW480 and SW620 colon cancer cells by investigating the possible role of mitophagy in mitochondria dysfunction, known to be induced by δVB in colorectal cancer cells [5]
Summary
Colorectal cancer (CRC) is the third most diagnosed cancer worldwide in 2020 with an estimated 1.8 million new cases [1]. The dietary δ-valerobetaine (δVB) (N,N,N-trimethyl-5-aminovaleric acid) is an emerging naturally occurring metabolite with antioxidant, anti-inflammatory and anticancer activities, displaying cytotoxic effects in colon cancer and head and neck squamous cell carcinomas [3,4,5,6]. In head and neck squamous cell carcinomas, δVB caused a severe inhibition of cell proliferation together with induction of apoptosis and cell cycle arrest in the G2/M phase [6]. Apoptosis and cell cycle arrest attenuation upon SIRT1 gene silencing supported the potential role of δVB as an epi-nutrient, acting as an anticancer agent through the modulation of SIRT1 [6]. In human colon cancer LoVo cells, δVB inhibited cell viability and induced cell cycle modulation, causing necrosis and a massive intracellular, extracellular and mitochondrial ROS production responsible for SIRT6 activation and apoptotic cell death [5]
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