Qing Li1, Wei Hu2, Wei-Xin Liu3, Liu-Yang Zhao3, Dan Huang2, Xiao-Dong Liu2, Hung Chan2, Yuchen Zhang2, Ju-Deng Zeng2, Olabisi Oluwabukola Coker3, Wei Kang4, Simon Siu Man Ng5, Lin Zhang1, Sunny Hei Wong3, Tony Gin2, Matthew Tak Vai Chan6, Jian-Lin Wu7, Jun Yu8, William Ka Kei Wu9. 1. Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. 2. Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, China. 3. State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. 4. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong, China. 5. Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China. 6. Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: mtvchan@cuhk.edu.hk. 7. State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Taipa, Macao. Electronic address: jlwu@must.edu.moand. 8. State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: junyu@cuhk.edu.hk. 9. Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: wukakei@cuhk.edu.hk.
Abstract
BACKGROUND & AIMS: Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention. METHODS: The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by β-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing. RESULTS: Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. β-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and β-galactosidase activity assay. β-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional β-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via β-galactosidase. β-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus. CONCLUSION: S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of β-galactosidase.
BACKGROUND & AIMS:Streptococcus thermophilus was identified to be depleted in patients with colorectal cancer (CRC) by shotgun metagenomic sequencing of 526 multicohort fecal samples. Here, we aim to investigate whether this bacterium could act as a prophylactic for CRC prevention. METHODS: The antitumor effects of S thermophilus were assessed in cultured colonic epithelial cells and in 2 murine models of intestinal tumorigenesis. The tumor-suppressive protein produced by S thermophilus was identified by mass spectrometry and followed by β-galactosidase activity assay. The mutant strain of S thermophilus was constructed by homologous recombination. The effect of S thermophilus on the gut microbiota composition was assessed by shotgun metagenomic sequencing. RESULTS: Oral gavage of S thermophilus significantly reduced tumor formation in both Apcmin/+ and azoxymethane-injected mice. Coincubation with S thermophilus or its conditioned medium decreased the proliferation of cultured CRC cells. β-Galactosidase was identified as the critical protein produced by S thermophilus by mass spectrometry screening and β-galactosidase activity assay. β-Galactosidase secreted by S thermophilus inhibited cell proliferation, lowered colony formation, induced cell cycle arrest, and promoted apoptosis of cultured CRC cells and retarded the growth of CRC xenograft. The mutant S thermophilus without functional β-galactosidase lost its tumor-suppressive effect. Also, S thermophilus increased the gut abundance of known probiotics, including Bifidobacterium and Lactobacillus via β-galactosidase. β-Galactosidase-dependent production of galactose interfered with energy homeostasis to activate oxidative phosphorylation and downregulate the Hippo pathway kinases, which partially mediated the anticancer effects of S thermophilus. CONCLUSION: S thermophilus is a novel prophylactic for CRC prevention in mice. The tumor-suppressive effect of S thermophilus is mediated at least by the secretion of β-galactosidase.
Authors: Yu Wang; Jiang Du; Xuemei Wu; Ahmed Abdelrehem; Yu Ren; Chao Liu; Xuan Zhou; Sinan Wang Journal: Mol Cancer Date: 2021-12-11 Impact factor: 27.401
Authors: Hamid A Bakshi; Gerry A Quinn; Alaa A A Aljabali; Faruck L Hakkim; Rabia Farzand; Mohamed M Nasef; Naji Abuglela; Prawej Ansari; Vijay Mishra; Ángel Serrano-Aroca; Murtaza M Tambuwala Journal: Pharmaceuticals (Basel) Date: 2021-11-23