The role of the natural compound naringenin in AMPK-mitochondria modulation and colorectal cancer inhibition

Abstract

BackgroundAlthough AMP-activated protein kinase (AMPK) has been extensively studied in cellular processes, the understanding of its substrates, downstream functions, contributions to cell fate and colorectal cancer (CRC) progression remains incomplete. PurposeThe aim of this study was to investigate the effects and mechanisms of naringenin on CRC. MethodsThe biological and cellular properties of naringenin and its anticancer activity were evaluated in CRC. In addition, the effect of combined treatment with naringenin and 5-fluorouracil on tumor growth in vitro and in vivo was evaluated. ResultsThe present study found that naringenin inhibits the proliferation of CRC and promote its apoptosis. Compared with the naringenin group, naringenin combined with 5-fluorouracil had significant effect on inhibiting cell proliferation and promoting its apoptosis. It is showed that naringenin activates AMPK phosphorylation and mitochondrial fusion in CRC. Naringenin combined with 5-fluorouracil significantly reduces cardiotoxicity and liver damage induced by 5-fluorouracil in nude mice bearing subcutaneous CRC tumors, and attenuates colorectal injuries in azoxymethane/DSS dextran sulfate (AOM/DSS)-induced CRC. The combination of these two drugs alters mitochondrial function by increasing reactive oxygen species (ROS) levels and decreasing the mitochondrial membrane potential (MMP), thereby stimulating AMPK/mTOR signaling. Mitochondrial dynamics are thereby regulated by activating the AMPK/p-AMPK pathway, and mitochondrial homeostasis is coordinated through increased mitochondrial fusion and reduced fission to activate apoptosis in cancer cells. ConclusionsOur data suggest that naringenin is important for inhibiting CRC proliferation, possibly through the AMPK pathway, to regulate mitochondrial function and induce apoptosis in CRC.