Previous reports have suggested that some probiotics inhibit tumorigenesis and cancer progression. However, the molecules involved have not yet been identified. Here, we show that the culture supernatant of Lactobacillus casei ATCC334 has a strong tumour-suppressive effect on colon cancer cells. Using mass spectrometry, we identify ferrichrome as a tumour-suppressive molecule produced by L. casei ATCC334. The tumour-suppressive effect of ferrichrome is greater than that of cisplatin and 5-fluorouracil, and ferrichrome has less of an effect on non-cancerous intestinal cells than either of those agents. A transcriptome analysis reveals that ferrichrome treatment induces apoptosis, which is mediated by the activation of c-jun N-terminal kinase (JNK). Western blotting indicates that the induction of apoptosis by ferrichrome is reduced by the inhibition of the JNK signalling pathway. This we demonstrate that probiotic-derived ferrichrome exerts a tumour-suppressive effect via the JNK signalling pathway.
Conifer and broadleaf trees emit volatile organic compounds in the summer. e major components of these emissions are volatile monoterpenes. Using solid phase microextraction ber as the adsorbant, monoterpenes were successfully detected and identi ed in forest air samples. Gas chromatography/mass chromatogram of monoterpenes in the atmosphere of a conifer forest and that of serum from subjects who were walking in a forest were found to be similar each other. e amounts of α-pinene in the subjects became several folds higher a er forest walking. e results indicate that monoterpenes in the atmosphere of conifer forests are transferred to and accumulate in subjects by inhalation while they are exposed to this type of environment.Please cite this article as: Mass Spectrom (Tokyo) 2015; 4(1): A0042
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.
Hypoxia inducible factor-1a (HIF-1a) has a central role in cellular oxygen-sensing, and its overexpression in many types of cancer is considered important in tumor progression. Thus, targeting HIF-1a production and activity has been of great therapeutic interest. In normoxic conditions, HIF-1a is hydroxylated by oxygen-dependent prolyl-hydroxylases, which require ferrous iron for its activity. The tumor suppressor protein von Hippel Lindau binds to the hydroxylated HIF-1a, which is then ubiquitinated and degraded by proteasomes. We focused on the physiological degradation machinery of HIF-1a mediated by prolyl hydroxylases. Previously, we identified a small molecule, LS081, that is capable of stimulating iron uptake into cells. In the present study, we aimed to inhibit the expression of HIF-1a protein and growth of hepatocellular carcinoma by using the iron-facilitating activity of LS081. In the human hepatocellular carcinoma cell lines Hep3B and HepG2, a combination of LS081 and ferric ammonium citrate (LS081/FeAC) inhibited HIF-1a protein expression but did not inhibit HIF-1a mRNA expression. A mutated HIF-1a protein, which has proline residues that were replaced with alanine and transfected into HEK293 cells, was not affected by the combination of LS081 and FeAC. Furthermore, the iron-facilitating activity of LS081 resulted in Hep3B and HepG2 growth inhibition in vitro and in vivo. These results indicate that the iron-facilitating activity of LS081 inhibits HIF-1a expression through prolyl-hydroxylation of HIF-1a and might have a therapeutic effect in the treatment of hepatocellular carcinoma. (Cancer Sci 2012; 103: 767-774) H ypoxia inducible factor-1 (HIF-1) is a transcription factor that enhances the expression of many genes, including those involved in angiogenesis, cell proliferation, glucose metabolism, erythropoiesis and cell survival. HIF-1 is composed of a and b subunits, where the b subunit is constitutively expressed and the a subunit is degraded under normoxic conditions despite the fact that it is continuously synthesized.(1,2) In the presence of oxygen, HIF-PHD1, 2 and 3 catalyze the iron-dependent hydroxylation of specific prolylresidues on HIF-1a. Once hydroxylated, HIF-1a binds to von Hippel Lindau tumor suppressor protein, is ubiquitinated and then degraded by proteasomes. However, under hypoxic conditions, HIF-1a is hydroxylated to a lesser extent and imported into the nucleus, where it binds to HIF-1b and other transcription factors and co-activators to transactivate a variety of genes containing the hypoxia response element. (3)(4)(5)(6) In most cancer cells, HIF-1a is overexpressed via either hypoxia-dependent or independent mechanisms, resulting in increased HIF transcriptional activity, (7)(8)(9)(10)(11) which helps the cancer cells to survive and grow by enhancing angiogenesis, motility and glycolysis. HIF activities are also involved in resistance to chemotherapy and radiation therapy.(7) Therefore, inhibition of HIF activities should be of importance in cancer treatment.The iron-...
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