Semaphoring 4D is required for the induction of antioxidant stress and anti-inflammatory effects of dihydromyricetin in colon cancer.

Semaphorin 4D (Sema4D) has been involved in cancer progression, the expression of which is associated with the poor clinical outcomes of some cancer patients. Dihydromyricetin (DMY) has antitumor potentials for different types of human cancer cells. However, the pharmacological effects of DMY on colon cancer (CC) or the regulatory effects of Sema4D on this process remain largely unknown. In the present study, we aimed to evaluate the effects of DMY on CC, and to elucidate the role of Sema4D in DMY-induced antitumor effects. DMY inhibited the proliferation and growth of Colo-205 colon cancer cells significantly in vivo and in vitro. DMY inhibited reactive oxygen species (ROS) and malondialdehyde (MDA) levels, but increased glutathione (GSH) level. Moreover, the activities of antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and heme oxygenase 1 (HO-1) were enhanced by DMY treatment in vitro, showing strong anti-oxidative stress effect. In addition, DMY inhibited the secretion of interleukin 1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF-α) in the supernatant of Colo-205 culture medium. Besides, the expressions of cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) were suppressed by DMY in dose-dependent manners in vivo, showing potent anti-inflammatory effect. Further investigations showed that DMY suppressed the expression and secretion of Sema4D in Colo-205 cells and tissues. Interestingly, overexpression of Sema4D significantly weakened the regulatory effects of DMY on oxidative stress. Furthermore, overexpression of Sema4D significantly attenuated the anti-inflammatory effects of DMY. Collectively, we drew a conclusion that the anti-colon cancer effect of DMY was attributed to its negative modulation on oxidative stress and inflammation via suppression of Sema4D. The findings broaden the width and depth of molecular mechanisms involved in the DMY action, facilitating the development of DMY in anti-colon cancer therapies.