Osthole impairs mitochondrial metabolism and the autophagic flux in colorectal cancer

Jisoo Song; Jiyeon Ham; Wonhyoung Park; Gwonhwa Song; Whasun Lim

doi:10.1016/j.phymed.2024.155383

Osthole impairs mitochondrial metabolism and the autophagic flux in colorectal cancer

Phytomedicine. 2024 Mar:125:155383. doi: 10.1016/j.phymed.2024.155383. Epub 2024 Jan 21.

Authors

Jisoo Song¹, Jiyeon Ham², Wonhyoung Park³, Gwonhwa Song⁴, Whasun Lim⁵

Affiliations

¹ Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Republic of Korea.
² Division of Animal and Dairy Science, Chungnam National University, Daejeon 34134, Republic of Korea.
³ Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
⁴ Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address: ghsong@korea.ac.kr.
⁵ Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon 16419, Republic of Korea. Electronic address: wlim@skku.edu.

PMID: 38295666
DOI: 10.1016/j.phymed.2024.155383

Abstract

Background: Osthole is active constituent of Cnidium monnieri (L.) Cuss. with various physiological functions including anti-inflammation and anti-lipedemic effects. However, the regulatory activity of osthole in colorectal cancer development, focusing on mitochondrial metabolism, is not well known.

Hypothesis/purpose: We hypothesized that osthole may suppress progression of colorectal cancer and aimed to determine the underlying mitochondrial metabolism and the autophagic flux.

Study design: In this study, we elucidated the mechanism of action of osthole in colorectal cancer using an in vivo azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model and an in vitro cell culture system.

Methods: AOM/DSS mouse model was established and analyzed the effects of osthole on survival rate, diseases activity index, number of tumor and histopathology. Then, cell based assays including viability, cell cycle, reactive oxygen species (ROS), apoptosis, calcium efflux, and mitochondrial function were analyzed. Moreover, osthole-mediated signaling was demonstrated by western blot analyses.

Results: Osthole effectively suppressed the growth of colorectal tumors and alleviated AOM/DSS-induced intestinal injury. Osthole restored the function of goblet cells and impaired the expression of Claudin1 and Axin1 impaired by AOM/DSS. In addition, osthole specifically showed cytotoxicity in colorectal carcinoma cells, but not in normal colon cells. Osthole decreased the ASC/caspase-1/IL-1β inflammasome pathway and induced mitochondrial dysfunction in redox homeostasis, calcium homeostasis. Furthermore, osthole inhibited both oxidative phosphorylation (OXPHOS) and glycolysis, leading to the suppression of ATP production. Moreover, via combination treatment with chloroquine (CQ), we demonstrated that osthole impaired autophagic flux, leading to apoptosis of HCT116 and HT29 cells. Finally, we elucidated that the functional role of tiRNA^HisGTG regulated by osthole directly affects the cellular fate of colon cancer cells.

Conclusion: These results suggest that osthole has the potential to manage progression of colorectal cancer by regulating autophagy- and mitochondria-mediated signal transduction.

Keywords: Autophagy; Colon cancer; Metabolism; Mitochondrial; tiRNA.

MeSH terms

Animals
Autophagy
Azoxymethane
Calcium*
Colorectal Neoplasms* / pathology
Coumarins*
Dextran Sulfate
Mice
Mitochondria

Substances

osthol
Calcium
Azoxymethane
Dextran Sulfate
Coumarins