Methylmalonic Acid at the Serum Level in the Elderly Contributes to Cell Growth Via Mitochondrial Dysfunction in Colorectal Cancer Cell Spheroids

Overview

Journal Biochem Biophys Rep

Date 2025 Jan 31

PMID 39886070

Authors

Arowu R Tanaka

Chiho Murakami

Hideya Yamamoto

Affiliations

Soon will be listed here.

Abstract

Methylmalonic acid (MMA) is a small molecule produced during the metabolism of propionate and branched-chain amino acids. Recently, it has been reported that the blood concentration of MMA increases with age and promotes lung cancer metastasis. However, little is known regarding its effects on cancers other than lung cancer. In the present study, we examined the effects of MMA on colorectal cancer cell spheroids. We found that MMA promoted the proliferation of colorectal cancer spheroids at physiological concentrations that can be exhibited by the elderly and induced mitochondrial reactive oxygen species generation, which in turn affected the promotion of cell growth. MMA treatment also induces a metabolic shift in the glycolytic system. These results suggest that MMA may promote cancer cell proliferation by decreasing mitochondrial function, inducing a metabolic shift, and provide new insights into the effects of aging on cancer.

References

Liu Y, Lu S, Wu L, Yang L, Yang L, Wang J . The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. 2023; 14(8):519. PMC: 10425449. DOI: 10.1038/s41419-023-06045-y. View

Vasan K, Werner M, Chandel N . Mitochondrial Metabolism as a Target for Cancer Therapy. Cell Metab. 2020; 32(3):341-352. PMC: 7483781. DOI: 10.1016/j.cmet.2020.06.019. View

Zhang L, Pitcher L, Yousefzadeh M, Niedernhofer L, Robbins P, Zhu Y . Cellular senescence: a key therapeutic target in aging and diseases. J Clin Invest. 2022; 132(15). PMC: 9337830. DOI: 10.1172/JCI158450. View

Luciani A, Devuyst O . Methylmalonyl acidemia: from mitochondrial metabolism to defective mitophagy and disease. Autophagy. 2020; 16(6):1159-1161. PMC: 7469617. DOI: 10.1080/15548627.2020.1753927. View

Head P, Meier J, Venditti C . New insights into the pathophysiology of methylmalonic acidemia. J Inherit Metab Dis. 2023; 46(3):436-449. PMC: 10715492. DOI: 10.1002/jimd.12617. View

Zhang Z, Jing D, Xuan B, Zhang Z, Wu W, Shao Z . Cellular senescence-driven transcriptional reprogramming of the axis activates the pathway and promotes osteosarcoma progression. Genes Dis. 2023; 11(2):952-963. PMC: 10491868. DOI: 10.1016/j.gendis.2023.02.028. View

Mensink M . Dietary protein, amino acids and type 2 diabetes mellitus: a short review. Front Nutr. 2024; 11:1445981. PMC: 11305142. DOI: 10.3389/fnut.2024.1445981. View

Tanaka A, Noguchi K, Fukazawa H, Igarashi Y, Arai H, Uehara Y . p38MAPK and Rho-dependent kinase are involved in anoikis induced by anicequol or 25-hydroxycholesterol in DLD-1 colon cancer cells. Biochem Biophys Res Commun. 2012; 430(4):1240-5. DOI: 10.1016/j.bbrc.2012.12.067. View

Gomes A, Ilter D, Low V, Drapela S, Schild T, Mullarky E . Altered propionate metabolism contributes to tumour progression and aggressiveness. Nat Metab. 2022; 4(4):435-443. PMC: 9050834. DOI: 10.1038/s42255-022-00553-5. View

10.

Hitsuda A, Dan R, Urakawa A, Hiraoka Y, Murakami C, Yamamoto H . 25-hydroxycholesterol-induced cell death via activation of ROCK/LIMK/cofilin axis in colorectal cancer cell spheroids. J Steroid Biochem Mol Biol. 2021; 216:106037. DOI: 10.1016/j.jsbmb.2021.106037. View

11.

Liu Y, Baba Y, Ishimoto T, Gu X, Zhang J, Nomoto D . Gut microbiome in gastrointestinal cancer: a friend or foe?. Int J Biol Sci. 2022; 18(10):4101-4117. PMC: 9274484. DOI: 10.7150/ijbs.69331. View

12.

Hinshaw D, Shevde L . The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 2019; 79(18):4557-4566. PMC: 6744958. DOI: 10.1158/0008-5472.CAN-18-3962. View

13.

Paoli P, Giannoni E, Chiarugi P . Anoikis molecular pathways and its role in cancer progression. Biochim Biophys Acta. 2013; 1833(12):3481-3498. DOI: 10.1016/j.bbamcr.2013.06.026. View

14.

Boutin M, Voss T, Titus S, Cruz-Gutierrez K, Michael S, Ferrer M . A high-throughput imaging and nuclear segmentation analysis protocol for cleared 3D culture models. Sci Rep. 2018; 8(1):11135. PMC: 6057966. DOI: 10.1038/s41598-018-29169-0. View

15.

Kakimoto M, Yamamoto H, Tanaka A . Spermine synthesis inhibitor blocks 25-hydroxycholesterol-induced- apoptosis via SREBP2 upregulation in DLD-1 cell spheroids. Biochem Biophys Rep. 2020; 22:100754. PMC: 7109571. DOI: 10.1016/j.bbrep.2020.100754. View

16.

Gorrini C, Harris I, Mak T . Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013; 12(12):931-47. DOI: 10.1038/nrd4002. View

17.

Yamada K, Sixt M . Mechanisms of 3D cell migration. Nat Rev Mol Cell Biol. 2019; 20(12):738-752. DOI: 10.1038/s41580-019-0172-9. View

18.

Chandler R, Venditti C . Gene Therapy for Methylmalonic Acidemia: Past, Present, and Future. Hum Gene Ther. 2019; 30(10):1236-1244. PMC: 6763959. DOI: 10.1089/hum.2019.113. View

19.

Li Z, Low V, Luga V, Sun J, Earlie E, Parang B . Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression. Nat Commun. 2022; 13(1):6239. PMC: 9584945. DOI: 10.1038/s41467-022-33862-0. View

20.

Shen Y, Chen C, Huang Y, Evans E, Cheng C, Chuang Y . Inhibition of glutaminolysis in combination with other therapies to improve cancer treatment. Curr Opin Chem Biol. 2021; 62:64-81. PMC: 8570367. DOI: 10.1016/j.cbpa.2021.01.006. View