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

BACKGROUND

Although 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.

PURPOSE: The aim of this study was to investigate the effects and mechanisms of naringenin on CRC.

METHODS

The 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.

RESULTS

The 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.

CONCLUSIONS

Our data suggest that naringenin is important for inhibiting CRC proliferation, possibly through the AMPK pathway, to regulate mitochondrial function and induce apoptosis in CRC.