Saccharomyces boulardii inhibits EGF receptor signaling and intestinal tumor growth in Apc(min) mice.
OBJECTIVE
Saccharomyces boulardii (Sb) is a probiotic yeast with anti-inflammatory and anti-microbial activities and has been used for decades in the prevention and treatment of a variety of human gastrointestinal disorders. We reported previously that Sb modulates host inflammatory responses through down-regulation of extracellular signal-regulated kinase (Erk)1/2 activities both in vitro and in vivo. The aim of this study was to identify upstream mediators responsible for extracellular signal-regulated kinase (Erk)1/2 inactivation and to examine the effects of Sb on tumor development in Apc(Min) mice.


METHODS
Signaling studies of colon cancer cells were done by western blot. Cell proliferation was measured by MTS and BrdU assay. Apoptosis was examined by flow cytometry, tunel assay and caspase assay. Apc(Min) mice were orally given Sb for 9 weeks before sacrifice for tumor analysis.


RESULTS
We found that the epidermal growth factor receptor (EGFR) was deactivated upon exposure to Sb, leading to inactivation of both the EGFR-Erk and EGFR-Akt pathways. In human colonic cancer cells, Sb prevented EGF-induced proliferation, reduced cell colony formation, and promoted apoptosis. HER-2, HER-3, and insulin-like growth factor-1 receptor were also found to be inactivated by Sb. Oral intake of Sb reduced intestinal tumor growth and dysplasia in C57BL/6J Min/+ (Apc(Min)) mice.


CONCLUSIONS
Thus, in addition to its anti-inflammatory effects, Sb inhibits EGFR and other receptor tyrosine kinase signaling and thereby may also serve a novel therapeutic or prophylactic role in intestinal neoplasia.
Chen
Xinhua
X
Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Fruehauf
Johannes
J
Goldsmith
Jeffrey D
JD
Xu
Hua
H
Katchar
Kianoosh K
KK
Koon
Hon-Wai
HW
Zhao
Dezheng
D
Kokkotou
Efi G
EG
Pothoulakis
Charalabos
C
Kelly
Ciarán P
CP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017491:Genes, APC; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D019936:Probiotics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012440:Saccharomyces; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3