Targeting the SIRT3/MnSOD and JNK/HMGB1/Beclin 1 Axes: Role of Apigenin in Multifaceted Metabolic Intervention in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most prevalent cancer worldwide. While chemotherapy remains the standard treatment approach, natural products have emerged as a promising alternative. Among these, apigenin, a natural flavonoid, has garnered significant attention due to its pro-oxidant and antioxidant properties in various types of cancer. This study aimed to assess the potential impact of apigenin in CRC treatment by targeting mitochondrial SIRT3, HMGB1, and beclin 1-mediated autophagy in a mouse model of CRC. We administered 20 mg/kg of dimethyl hydrazine (DMH) intraperitoneally once weekly for 20 weeks to induce CRC in C57BL/6 mice. After 6 weeks of initiating the study, apigenin was intragastrically co-administered by oral gavage at 25 and 50 mg/kg until the end of week 20. The results revealed significant weight loss, shortening of the colon, and diarrhea in DMH-induced CRC, which are considered the marks of CRC. In addition, histopathological examination revealed dysplastic changes in the DMH-treated group, while no dysplasia was found in the apigenin-treated CRC groups. Importantly, the administration of apigenin to DMH-treated animals has led to a significant reduction of SIRT3 and MnSOD expression levels with a significant increase in LC3-II at either dose and a significant dose-dependent increase in the levels of MDA, c-JNK, HMGB1, and beclin 1 compared to the DMH-treated group. In conclusion, apigenin may have a promising role in suppressing DMH-induced CRC. It elicits a pro-oxidant activity by suppressing the gene expression of SIRT3 and subsequently, its target MnSOD, resulting in increased reactive oxygen species (ROS) and lipid peroxidation. The released ROS, in turn, activates JNK-mediated autophagy by enhancing HMGB1, beclin 1, and LC3-II protein levels.