Probiotic Aspergillus oryzae produces anti-tumor mediator and exerts anti-tumor effects in pancreatic cancer through the p38 MAPK signaling pathway

Abstract

Intake of probiotics or fermented food produced by some probiotic bacteria is believed to exert anti-tumor functions in various cancers, including pancreatic cancer, because several studies have demonstrated the anti-tumor effects of probiotic bacteria in vitro and in vivo in animal carcinogenesis models. However, the mechanisms underlying the anticancer effects of probiotics on pancreatic cancer have not been clarified. In this study, we assessed the anti-tumor effects of probiotic bacteria against pancreatic cancer cells. Among the known probiotic bacteria, Aspergillus oryzae exhibited a strong pancreatic tumor suppression effect. The culture supernatant of A. oryzae was separated by HPLC. Heptelidic acid was identified as an anti-tumor molecule derived from A. oryzae by LC–MS and NMR analysis. The anti-tumor effect of heptelidic acid was exhibited in vitro and in vivo in a xenograft model of pancreatic cancer cells. The anti-tumor effect of heptelidic acid was exerted by the p38 MAPK signaling pathway. Heptelidic acid traverses the intestinal mucosa and exerts anti-tumor effects on pancreatic cancer cells. This is a novel anti-tumor mechanism induced by beneficial bacteria against pancreatic cancer in which bacterial molecules pass through the intestinal tract, reach the extra-intestinal organs, and then induce apoptosis via an inducible signaling pathway.

Connecting the Human Microbiome and Pancreatic Cancer

“…are gram-positive anaerobes categorized as “good bacteria” which metabolizes carbohydrates and competes against more harmful bacteria within the gut. Chen et al found that the probiotic Lactobacillus synergizes with gemcitabine in an in vivo pancreatic cancer model where Konishi et al found that Aspergillus oryzae was found to have anti-tumor properties through altering MAPK/ERK signaling [ 124 , 125 ]. Pancreatic cancer was also found to be inhibited by the ferrichrome compound, an iron molecule that can be found in probiotics, and was shown to be effective in 5-FU resistant cells [ 126 ].…”

Gut Dysbiosis in Pancreatic Diseases: A Causative Factor and a Novel Therapeutic Target

“…In addition, probiotic-treated super-charged NK cells could prevent the growth of pancreatic tumors through lysis and differentiation in humanized-BLT mice ( 206 ). The MAPK-p38 and transforming growth factor-β (TGF-β) signaling pathways have been hypothesized to be the mechanisms by which probiotics exert their anti-tumor effects ( 207 , 208 ). Whether probiotics have a role in slowing or inhibiting the progression of pancreatic cancer needs to be further investigated and warrants future preclinical and clinical studies.…”

GAPDH in neuroblastoma: Functions in metabolism and survival

“…As a result, koningic acid enhances the toxicity of H 2 O 2 -mediated oxidative damage in smooth muscle cells ( 55 ). Koningic acid was isolated from three different fungi from soil ( 56 ) and inhibits GAPDH ( 57 ) with resulting activity towards a variety of cancer cell types ( 58 – 60 ), including neuroblastoma ( 61 ). In some cases, koningic acid reverses drug resistance in cancer ( 62 ).…”