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

  • Phytomedicine. 2024 Aug:131:155786. doi: 10.1016/j.phymed.2024.155786.
Dan Wang  1 ,  Yue Zhou  1 ,  Li Hua  1 ,  Meichun Hu  1 ,  Ni Zhu  1 ,  Yifei Liu  2 ,  Yanhong Zhou  3
Affiliations
  • 1. School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, China.
  • 2. School of Biomedical Engineering and Imaging, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, China. Electronic address: [email protected].
  • 3. School of Basic Medical Sciences, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei 437100, China. Electronic address: [email protected].
PMID: 38875812 DOI: 10.1016/j.phymed.2024.155786
Abstract

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.

Keywords
AMPK; Apoptosis; Colorectal cancer; Mitochondria; Mouse model; Naringenin.
Products