Human α-defensin 5 suppressed colon cancer growth by targeting PI3K pathway

Qiao, Qiao; Bai, Ruixia; Song, Wanying; Gao, Haining; Zhang, Minyu; Lü, Junhong; Zhang, Xuan; Péng, Shigē; Zhang, Qian; Zhao, Pengwei

doi:10.1016/j.yexcr.2021.112809

Cited by 9 publications

(6 citation statements)

References 51 publications

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“…In contrast, hyperactivation of the Wnt signaling pathway, especially by mutation in the adenomatous polyposis coli (APC) gene, has been associated with colorectal carcinogenesis [ 69 ]. However, there is evidence that overexpression of Defa5 reduced tumorigenesis in mice by directly binding phosphoinositide 3-kinases (PI3K) subunits [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Human α-Defensin 51–9 and Human β-Defensin 2 Improve Metabolic Parameters and Gut Barrier Function in Mice Fed a Western-Style Diet

Filipe Rosa,

Rings,

Stolzer

et al. 2023

IJMS

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Obesity and metabolic comorbidities are associated with gut permeability. While high-fructose and Western-style diet (WSD) disrupt intestinal barrier function, oral administration of human α-defensin 5 (HD5) and β-defensin 2 (hBD2) is believed to improve intestinal integrity and metabolic disorders. Eighty-four male C57BL/6J mice were fed a WSD or a control diet (CD) ± fructose (F) for 18 weeks. In week 13, mice were randomly divided into three intervention groups, receiving defensin fragment HD51–9, full-length hBD2, or bovine serum albumin (BSA)-control for six weeks. Subsequently, parameters of hepatic steatosis, glucose metabolism, and gut barrier function were assessed. WSDF increased body weight and hepatic steatosis (p < 0.01) compared to CD-fed mice, whereas peptide intervention decreased liver fat (p < 0.05) and number of hepatic lipid droplets (p < 0.01) compared to BSA-control. In addition, both peptides attenuated glucose intolerance by reducing blood glucose curves in WSDF-fed mice. Evaluation of gut barrier function revealed that HD51–9 and hBD2 improve intestinal integrity by upregulating tight junction and mucin expression. Moreover, peptide treatment restored ileal host defense peptides (HDP) expression, likely by modulating the Wnt, Myd88, p38, and Jak/STAT pathways. These findings strongly suggest that α- and β-defensin treatment improve hepatic steatosis, glucose metabolism, and gut barrier function.

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Section: Discussionmentioning

confidence: 99%

Human α-Defensin 51–9 and Human β-Defensin 2 Improve Metabolic Parameters and Gut Barrier Function in Mice Fed a Western-Style Diet

Filipe Rosa,

Rings,

Stolzer

et al. 2023

IJMS

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show abstract

“…On the other hand, the work of Wu et al, showed that a drastic downregulation of DEFA5 can be detected in patients with gastric carcinoma. These findings along with experimental data demonstrating a tumor cell growth inhibitory effect of DEFA5 point to a role of DEFA5 as a tumor suppressor [ 34 , 35 ]. Considering its tumor-suppressive function and its known immunomodulating role of DEFA5, the detection of DEFA5 even in healthy donors is reasonable and has also been reported earlier [ 32 ].…”

Section: Discussionmentioning

confidence: 82%

“…Moreover, we recently demonstrated elevated DEFA5 mRNA expression in blood-derived MNC of CRC patients compared to patients with benign diseases of this organ system and healthy donors [ 32 ]. However, despite some reports on the function of DEFA5 in the regulation of cell growth and apoptosis, its role in tumorigenesis is not yet well understood [ 33 , 34 , 35 ]. The fact that DEFA5 can negatively affect E-cadherin expression in esophageal squamous cells suggests that it may promote the dissemination of EC cells from the primary context and may thereby play a crucial role in EC progression [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

Detection of Circulating and Disseminated Tumor Cells and Their Prognostic Value under the Influence of Neoadjuvant Therapy in Esophageal Cancer Patients

Richter

Röder

Möller

et al. 2022

Cancers

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Detection of circulating (CTC) or disseminated tumor cells (DTC) are correlated with negative prognosis in esophageal cancer (EC) patients. In this study, DTC- and CTC-associated markers CK20 and DEFA5 were determined by RT-PCR in EC patients and correlated with clinical parameters to determine their prognostic impact. The blood and bone marrow (BM) of 216 EC patients after tumor resection with or without neoadjuvant therapy and as control blood samples from 38 healthy donors and BM from 24 patients with non-malignant diseases were analyzed. Both markers were detected in blood and BM of EC patients and the control cohort. A cut-off value was determined to define marker positivity for correlation with clinical data. CK20 expression was detected in 47/206 blood samples and in 49/147 BM samples of EC patients. DEFA5 positivity was determined in 96/206 blood samples and 98/147 BM samples, not correlating with overall survival (OS). However, CK20 positivity in BM and DEFA5 negativity in blood were associated with reduced OS in EC patients without neoadjuvant therapy, while in patients with neoadjuvant therapy DEFA5 positivity in BM was associated with improved OS. Overall, our study suggests DEFA5 as a prognostic biomarker in liquid biopsies of EC patients which requires further validation.

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“…In nude mice, overexpression of this gene suppressed tumor growth. The mechanisms behind its tumor suppressive effect involves phosphoinositide 3-kinase, as DEFA5 binds directly to its signaling complex, leading to delayed cell growth and metastasis [ 43 ]. Interestingly, hBD-1 is able to alter human epidermal growth factor receptor 2 (HER2) signal transduction and urine-derived hBD-1 was able to suppress bladder cancer growth [ 44 ].…”

Section: Direct Effect On Tumor Cellsmentioning

confidence: 99%

Role of Defensins in Tumor Biology

Adyns

Proost

Struyf

2023

IJMS

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Defensins have long been considered as merely antimicrobial peptides. Throughout the years, more immune-related functions have been discovered for both the α-defensin and β-defensin subfamily. This review provides insights into the role of defensins in tumor immunity. Since defensins are present and differentially expressed in certain cancer types, researchers started to unravel their role in the tumor microenvironment. The human neutrophil peptides have been demonstrated to be directly oncolytic by permealizing the cell membrane. Further, defensins can inflict DNA damage and induce apoptosis of tumor cells. In the tumor microenvironment, defensins can act as chemoattractants for subsets of immune cells, such as T cells, immature dendritic cells, monocytes and mast cells. Additionally, by activating the targeted leukocytes, defensins generate pro-inflammatory signals. Moreover, immuno-adjuvant effects have been reported in a variety of models. Therefore, the action of defensins reaches beyond their direct antimicrobial effect, i.e., the lysis of microbes invading the mucosal surfaces. By causing an increase in pro-inflammatory signaling events, cell lysis (generating antigens) and attraction and activation of antigen presenting cells, defensins could have a relevant role in activating the adaptive immune system and generating anti-tumor immunity, and could thus contribute to the success of immune therapy.

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Human α-defensin 5 suppressed colon cancer growth by targeting PI3K pathway

Cited by 9 publications

References 51 publications

Human α-Defensin 51–9 and Human β-Defensin 2 Improve Metabolic Parameters and Gut Barrier Function in Mice Fed a Western-Style Diet

Human α-Defensin 51–9 and Human β-Defensin 2 Improve Metabolic Parameters and Gut Barrier Function in Mice Fed a Western-Style Diet

Detection of Circulating and Disseminated Tumor Cells and Their Prognostic Value under the Influence of Neoadjuvant Therapy in Esophageal Cancer Patients

Role of Defensins in Tumor Biology

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