Ferrichrome identified from <i>Lactobacillus casei ATCC334</i> induces apoptosis through its iron-binding site in gastric cancer cells

Ijiri, Masami; Fujiya, Mikihiro; Konishi, Hiroaki; Tanaka, Hiroki; Ueno, Nobuhiro; Moriichi, Kentaro; Sasajima, Junpei; Ikuta, Katsuya; Okumura, Toshikatsu

doi:10.1177/1010428317711311

Cited by 25 publications

(20 citation statements)

References 29 publications

(46 reference statements)

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“…E. coli Nissle), infections and cancer (e.g. ferrichrome) [79–83]. Specifically, the understanding of the antagonistic relationship between siderophores and Lcn2 has allowed these iron-chelators to be utilized for both their canonical and non-canonical functions in various therapeutics.…”

Section: Therapeuticsmentioning

confidence: 99%

The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity

2019

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Iron is necessary for the survival of almost all aerobic organisms. In the mammalian host, iron is a required cofactor for the assembly of functional iron-sulfur (Fe-S) cluster proteins, heme-binding proteins and ribonucleotide reductases that regulate various functions, including heme synthesis, oxygen transport and DNA synthesis. However, the bioavailability of iron is low due to its insolubility under aerobic conditions. Moreover, the host coordinates a nutritional immune response to restrict the accessibility of iron against potential pathogens. To counter nutritional immunity, most commensal and pathogenic bacteria synthesize and secrete small iron chelators termed siderophores. Siderophores have potent affinity for iron, which allows them to seize the essential metal from the host iron-binding proteins. To safeguard against iron thievery, the host relies upon the innate immune protein, lipocalin 2 (Lcn2), which could sequester catecholate-type siderophores and thus impede bacterial growth. However, certain bacteria are capable of outmaneuvering the host by either producing “stealth” siderophores or by expressing competitive antagonists that bind Lcn2 in lieu of siderophores. In this review, we summarize the mechanisms underlying the complex iron tug-of-war between host and bacteria with an emphasis on how host innate immunity responds to siderophores.

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Section: Therapeuticsmentioning

confidence: 99%

The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity

2019

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“…It has also been reported that an ER-associated molecule, scotin, induced p53 activation under excessive endoplasmic reticulum (ER) stress, thereby inducing cell apoptosis ( 33 ). Our previous studies have reported that ferrichrome upregulated ER stress, leading to the activation of the JNK-DDIT3 pathway, and subsequent induction of apoptosis in colorectal and gastric cancer cells ( 19 , 20 ). Collectively, probiotic-derived ferrichrome is hypothesized to expose cancer cells to ER stress, and thereby induce apoptosis via the activation of ER stress-associated pathways, including JNK-DDIT3 and/or p53, which is a novel mechanism of the antitumor function of probiotic bacteria.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study reported that inorganic polyphosphate exhibited tumor-suppressive effects via the activation of ERK (18). Our previous studies also revealed that ferrichrome, identified from L. casei ATCC334, exhibited tumor-suppressive effects in colorectal cancer cells and gastric cancer cells through the induction of DNA damage inducible transcript 3 (DDIT3)-mediated apoptosis (19,20). Ferrichrome was identified as a bacterial iron-chelating agent, as bacteria acquire Fe 3+ from the external environment (21).…”

Section: Introductionmentioning

confidence: 99%

Probiotic‑derived ferrichrome inhibits the growth of refractory pancreatic cancer cells

et al. 2020

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Pancreatic cancer is associated with a poor prognosis due to challenges in early detection, severe progression of the primary tumor, metastatic lesions, and resistance to antitumor agents. However, previous studies have indicated a relationship between the microbiome and pancreatic cancer outcomes. Our previous study demonstrated that ferrichrome derived from Lactobacillus casei, a probiotic bacteria, exhibited tumor-suppressive effects in colorectal and gastric cancer, and that the suppressive effects were stronger than conventional antitumor agents, such as 5-fluorouracil (5-FU) and cisplatin, suggesting that certain probiotics exert antitumorigenic effects. However, whether or not probiotic-derived molecules, including ferrichrome, exert a tumor-suppressive effect in other gastrointestinal tumors, such as pancreatic cancer, remains unclear. In the present study, it was demonstrated that probiotic-derived ferrichrome inhibited the growth of pancreatic cancer cells, and its tumor-suppressive effects were further revealed in 5-FU-resistant pancreatic cancer cells in vitro and in vivo in a mouse xenograft model. Ferrichrome inhibited the progression of cancer cells via dysregulation of the cell cycle by activating p53. DNA fragmentation and cleavage of poly (ADP-ribose) polymerase were induced by ferrichrome treatment, suggesting that ferrichrome induced apoptosis in pancreatic cancer cells. A transcriptome analysis revealed that the expression p53-associated mRNAs was significantly altered by ferrichrome treatment. Thus, the tumor-suppressive effects of probiotics may mediated by probiotic-derived molecules, such as ferrichrome, which may have applications as an antitumor drug, even in refractory and 5-FU-resistant pancreatic cancer.

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“…Ferrichrome is known as a small high affinity and iron-chelating molecules siderophore, which is created by Lactobacillus casei ATCC334; nowadays, it is regarded as an anti-cancer molecule. Ferrichrome induces apoptosis by activating the c-Jun N-terminal kinase (JNK)-DNA damage-inducible transcript 3 (DDIT3) pathways and upregulating the cleavage of poly adenosine diphosphate-ribose polymerase (PARP) in CRC cells [42]. Ferrichrome is safe for non-cancerous cells, as the growth of IEC-18 and primary cultured cells that belong to the mouse's small intestine are not influenced by it.…”

Section: Ferrichromementioning

confidence: 99%

The Inhibitory Effect of Gut Microbiota and Its Metabolites on Colorectal Cancer

Chen

2020

J. Microbiol. Biotechnol.

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CRC is the second leading cause of cancer-related death worldwide. There are about 700,000 people dying of CRC every year [1]. CRC is considered as one of the health care challenges, and it is related to genetic encoding and more significantly, about 70% of all CRC cases are influential by environmental aspects through a couple of years, including diets, lifestyle, metabolic syndrome and gut microecology, etc [2]. Gut microbiota consists mainly of bacteria, fungi, bacteria and viruses that populate the gut, primarily the large intestine. About 90% of gut microbiota is composed of two phyla, that is, Firmicutes and Bacteroidetes, in healthy human [3]. With the development of technology, we have a better understanding of the composition, function and metabolic characteristics of the human gut microbiota [4]. There is growing evidence that commensal bacteria of human being is the vital determinant of healthy or pathological conditions, including cancer [5]. Metagenomics and metabolomics researches stressed the double effect of the gut microbiota in tumorigenesis (either inhibit cancer or promote cancer) [6]. Gut microbiota exerts the significant effects on host by producing vitamins, metabolizing dietary compounds, inhibiting the expansion and systemic infiltration of gut pathogens [7]. Other results underline the complicacy and two-way of the association between microbiota and cancer. The progression of cancer may change the microbiota. Meanwhile, altering microbiota may influence cancer development [8]. Undoubtedly, the occurrence of CRC is also related to the function of some gut microbiota constituents whose role serves as initiator or inhibitor [9]. Although we have studied the association for many years, only a small part feature was exposed. In this essay, we will list some current results about cellular and microbial metabolism regulation in CRC, concentrating on the mechanistic association of gut microbiota metabolites and constituents with CRC prevention or treatment. The Mechanism of Gut Microbiota against Cancer Recently evidences from in vitro and animal model to clinical trials, as well as the use of selected gut microbiota for preventing or treating CRC, have demonstrated the antiproliferative activity. The selected gut microbiota mainly includes Lactobacillus, Bifidobacterium sp., Enterococcus faecalis and so on. Many studies based on human cancer cells or cell line demonstrated that gut microbiota processes the function of restraining cell proliferation or stimulating apoptosis in CRC (Table 1). In the main animal models studied from 2017 to 2019, N-methyl-Nnitrosourea (MNU), 1,2-dimethylhydrazine (DMH) and azoxymethane (AOM) were used as CRC inductor respectively. The specific gut microbiota studied in these models is shown in Table 2. In human studies conducted between 2015 and 2017, several double-blind, randomized and placebo controlled researches indicated that the addition of specific gut microbiota is effective in treating, which reduces the postoperative complications of CRC Colorectal cance...

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Ferrichrome identified from Lactobacillus casei ATCC334 induces apoptosis through its iron-binding site in gastric cancer cells

Cited by 25 publications

References 29 publications

The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity

The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity

Probiotic‑derived ferrichrome inhibits the growth of refractory pancreatic cancer cells

The Inhibitory Effect of Gut Microbiota and Its Metabolites on Colorectal Cancer

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