LZZAY01 Accelerated Autophagy and Apoptosis in Colon Cancer Cells and Improved Gut Microbiota in CAC Mice

Overview

Journal Microbiol Spectr

Date 2025 Jan 10

PMID 39792005

Authors

Wenhong Yang

Tao Li

Shixiang An

Rong Chen

Yuxin Zhao

Jiaxian Cui

Mingyu Zhang

Jingkun Lu

Yunpeng Tian

Lili Bao

Pengwei Zhao

Affiliations

Soon will be listed here.

Abstract

Colorectal cancer (CRC) is one of the malignant tumors globally, with high morbidity and mortality rates. The mainstay treatment of CRC includes surgery, radiotherapy, and chemotherapy. However, these treatments are associated with a high recurrence rate, poor prognosis, and highly toxic side effects. The probiotics have the potential to prevent CRC, and they display a favorable safety performance. Probiotics could provide a potential strategy to prevent and treat CRC. The impact of LZZAY01 on cancer cell lines CT-26, HCT-116, and SW-620 was evaluated by conducting cytotoxicity and clonogenicity tests. A model of colitis-associated cancer (CAC) was established in C57BL/6j mice following induction with AOM/DSS. The levels of autophagy and apoptosis proteins, tight junction proteins, and inflammatory factors were detected by western blotting, immunofluorescence assay, and enzyme-linked immunosorbent assay. High-throughput sequencing of gut 16S rRNA was performed to analyze the abundance and diversity of the gut microbiome. LZZAY01, a new strain of , was certified by an evolutionary tree and average nucleotide identity. LZZAY01 enhanced autophagy and apoptosis in CT-26, HCT-116, and SW-620 cell lines. It preserved the integrity of the intestinal barrier by regulating the tight junction protein ZO-1 and claudin-1. The tumor necrosis factor-α and interleukin-6 were reduced by LZZAY01. The abundance and diversity of the intestinal microbiota were enhanced, especially the beneficial bacterial species maintaining the balance of the intestinal flora such as and . LZZAY01 improved CAC suppressing the growth of colon cancer cells, promoting autophagy and apoptosis, enhancing intestinal tight junctions, reducing intestinal barrier degradation, modifying the gut microbiota abundance, and decreasing inflammatory reactions.IMPORTANCEAlthough similar probiotics have been shown to have anticancer potential in colorectal cancer (CRC), there is a paucity of research related to the preventive function of probiotics against CRC. And there are fewer studies about the mechanism of probiotics' preventive effects on CRC. The regulation of tumor cell proliferation and apoptosis by the active ingredients of probiotics may be one of the mechanisms of their prevention of CRC. In this study, we explored the effects of LZZAY01 on autophagy and apoptosis of colon cancer cells and and proposed a possible mechanism for the prevention of CRC by probiotics.

References

Kang K, Piao M, Hyun Y, Zhen A, Cho S, Ahn M . Luteolin promotes apoptotic cell death via upregulation of Nrf2 expression by DNA demethylase and the interaction of Nrf2 with p53 in human colon cancer cells. Exp Mol Med. 2019; 51(4):1-14. PMC: 6465248. DOI: 10.1038/s12276-019-0238-y. View

El Tekle G, Andreeva N, Garrett W . The Role of the Microbiome in the Etiopathogenesis of Colon Cancer. Annu Rev Physiol. 2024; 86:453-478. DOI: 10.1146/annurev-physiol-042022-025619. View

Peng B, Singh A, Chan C, Deng Y, Li P, Su C . AGA induces sub-G1 cell cycle arrest and apoptosis in human colon cancer cells through p53-independent/p53-dependent pathway. BMC Cancer. 2023; 23(1):1. PMC: 9808967. DOI: 10.1186/s12885-022-10466-x. View

Rawla P, Sunkara T, Barsouk A . Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019; 14(2):89-103. PMC: 6791134. DOI: 10.5114/pg.2018.81072. View

Keum N, Giovannucci E . Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019; 16(12):713-732. DOI: 10.1038/s41575-019-0189-8. View

Resnick M, Konkin T, Routhier J, Sabo E, Pricolo V . Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study. Mod Pathol. 2004; 18(4):511-8. DOI: 10.1038/modpathol.3800301. View

Hu G, Song P, Li N, Chen W, Lei Q, Yu S . AIM2 contributes to the maintenance of intestinal integrity via Akt and protects against Salmonella mucosal infection. Mucosal Immunol. 2016; 9(5):1330-9. DOI: 10.1038/mi.2015.142. View

Audisio A, Fazio R, Dapra V, Assaf I, Hendlisz A, Sclafani F . Neoadjuvant chemotherapy for early-stage colon cancer. Cancer Treat Rev. 2023; 123:102676. DOI: 10.1016/j.ctrv.2023.102676. View

Yan J, Duan W, Gao Q, Mao T, Wang M, Duan J . ENPP2 inhibitor improves proliferation in AOM/DSS-induced colorectal cancer mice via remodeling the gut barrier function and gut microbiota composition. Pharmacol Res. 2023; 195:106877. DOI: 10.1016/j.phrs.2023.106877. View

10.

Saxami G, Karapetsas A, Chondrou P, Vasiliadis S, Lamprianidou E, Kotsianidis I . Potentially probiotic Lactobacillus strains with anti-proliferative activity induce cytokine/chemokine production and neutrophil recruitment in mice. Benef Microbes. 2017; 8(4):615-623. DOI: 10.3920/BM2016.0202. View

11.

Liu X, Zhao M, Sun X, Meng Z, Bai X, Gong Y . Autophagic Flux Unleashes GATA4-NF-B Axis to Promote Antioxidant Defense-Dependent Survival of Colorectal Cancer Cells under Chronic Acidosis. Oxid Med Cell Longev. 2022; 2021:8189485. PMC: 8720590. DOI: 10.1155/2021/8189485. View

12.

Roca-Lema D, Quiroga M, Khare V, Diaz-Diaz A, Barreiro-Alonso A, Rodriguez-Alonso A . Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease. Sci Rep. 2022; 12(1):17571. PMC: 9584894. DOI: 10.1038/s41598-022-22295-w. View

13.

Wang C, Li W, Wang H, Ma Y, Zhao X, Zhang X . Saccharomyces boulardii alleviates ulcerative colitis carcinogenesis in mice by reducing TNF-α and IL-6 levels and functions and by rebalancing intestinal microbiota. BMC Microbiol. 2019; 19(1):246. PMC: 6836350. DOI: 10.1186/s12866-019-1610-8. View

14.

Bi Z, Cui E, Yao Y, Chang X, Wang X, Zhang Y . Recombinant Carrying Endostatin Protein Alleviates Dextran Sodium Sulfate-Induced Colitis and Colon Cancer in Rats. Front Microbiol. 2022; 13:927277. PMC: 9280188. DOI: 10.3389/fmicb.2022.927277. View

15.

Tiptiri-Kourpeti A, Spyridopoulou K, Santarmaki V, Aindelis G, Tompoulidou E, Lamprianidou E . Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells. PLoS One. 2016; 11(2):e0147960. PMC: 4744000. DOI: 10.1371/journal.pone.0147960. View

16.

Kushwaha K, Muriana P . Comparison of invasiveness among surface-adherent variants of Listeria monocytogenes in Caco-2 cell culture assays. Int J Food Microbiol. 2010; 138(1-2):166-71. DOI: 10.1016/j.ijfoodmicro.2009.11.024. View

17.

Zhang M, Fan X, Fang B, Zhu C, Zhu J, Ren F . Effects of Lactobacillus salivarius Ren on cancer prevention and intestinal microbiota in 1, 2-dimethylhydrazine-induced rat model. J Microbiol. 2015; 53(6):398-405. DOI: 10.1007/s12275-015-5046-z. View

18.

Kuppusamy P, Kim D, Soundharrajan I, Park H, Jung J, Yang S . Low-Carbohydrate Tolerant LAB Strains Identified from Rumen Fluid: Investigation of Probiotic Activity and Legume Silage Fermentation. Microorganisms. 2020; 8(7). PMC: 7409070. DOI: 10.3390/microorganisms8071044. View

19.

Fan X, Guo H, Teng C, Yang X, Qin P, Richel A . Supplementation of quinoa peptides alleviates colorectal cancer and restores gut microbiota in AOM/DSS-treated mice. Food Chem. 2022; 408:135196. DOI: 10.1016/j.foodchem.2022.135196. View

20.

Kawauchiya T, Takumi R, Kudo Y, Takamori A, Sasagawa T, Takahashi K . Correlation between the destruction of tight junction by patulin treatment and increase of phosphorylation of ZO-1 in Caco-2 human colon cancer cells. Toxicol Lett. 2011; 205(2):196-202. DOI: 10.1016/j.toxlet.2011.06.006. View