Correlation of two distinct metastasis-associated proteins, MTA1 and S100A4, in angiogenesis for promoting tumor growth

Ishikawa, Mizuho; Osaki, Mitsuhiko; Yamagishi, Masaaki; Onuma, Kunishige; Ito, Hisao; Okada, Futoshi; Endo, Hiroki

doi:10.1038/s41388-019-0748-z

Cited by 22 publications

(24 citation statements)

References 33 publications

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“…ZsGreen were established as described previously 38 . The characteristics of mouse endothelial MSS31 cells were described previously [39][40][41] . The cells were usually cultured in high-glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal bovine serum and 40 μg/ml gentamycin in a humidified atmosphere with 21% O 2 /5% CO 2 .…”

Section: Discussionmentioning

confidence: 99%

Obesity reduces the anticancer effect of AdipoRon against orthotopic pancreatic cancer in diet-induced obese mice

Takenaga

Akimoto

Koshikawa

et al. 2021

Sci Rep

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The antidiabetic adiponectin receptor agonist AdipoRon has been shown to suppress the tumour growth of human pancreatic cancer cells. Because obesity and diabetes affect pancreatic cancer progression and chemoresistance, we investigated the effect of AdipoRon on orthotopic tumour growth of Panc02 pancreatic cancer cells in DIO (diet-induced obese) prediabetic mice. Administration of AdipoRon into DIO mice fed high-fat diets, in which prediabetic conditions were alleviated to some extent, did not reduce either body weight or tumour growth. However, when the DIO mice were fed low-fat diets, body weight and the blood leptin level gradually decreased, and importantly, AdipoRon became effective in suppressing tumour growth, which was accompanied by increases in necrotic areas and decreases in Ki67-positive cells and tumour microvessels. AdipoRon inhibited cell growth and induced necrotic cell death of Panc02 cells and suppressed angiogenesis of endothelial MSS31 cells. Insulin and IGF-1 only slightly reversed the AdipoRon-induced suppression of Panc02 cell survival but had no effect on the AdipoRon-induced suppression of MSS31 cell angiogenesis. Leptin significantly ameliorated AdipoRon-induced suppression of angiogenesis through inhibition of ERK1/2 activation. These results suggest that obesity-associated factors weaken the anticancer effect of AdipoRon, which indicates the importance of weight loss in combating pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Obesity reduces the anticancer effect of AdipoRon against orthotopic pancreatic cancer in diet-induced obese mice

Takenaga

Akimoto

Koshikawa

et al. 2021

Sci Rep

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“…We previously reported the mechanism of tube formation by MTA1, wherein MTA1 interacts with S100A4 and changes the phosphorylation state of NMIIa (Ishikawa et al, 2019). Therefore, we examined whether inhibition of tube formation by MTA1 knockout and its restoration by MTA1 overexpression was correlated with the amount of MTA1–S100A4 complex and the phosphorylation state of NMIIa.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, we demonstrated that MTA1 knockdown induced a decrease in S100 calcium-binding protein A4 (S100A4) expression and an increase in phosphorylated non-muscle myosin heavy chain IIa (NMIIa). This phosphorylation level of NMIIa may influence the formation of tube structures via altered cytoskeletal dynamics in endothelial cells (Ishikawa et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Endothelial metastasis-associated protein 1 (MTA1) is an essential molecule for angiogenesis

Ishikawa

Osaki

Uno³

et al. 2021

Preprint

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Our previous study revealed that metastasis-associated protein 1 (MTA1), expressed in endothelial cells acts as a factor promoting tube formation. In this study, we aimed to clarify the importance of MTA1 in tube formation using MTA1-knockout endothelial cells (MTA1-KO MSS31 cells). Tube formation was strongly suppressed in MTA1-KO MSS31 cells, whereas MTA1-overexpressed MTA1-KO MSS31 cells regained the ability to form tube-like structures. Furthermore, MTA1-KO MSS31 cells showed higher phosphorylation of non-muscle myosin heavy chain IIa (NMIIa), which resulted in suppression of tube formation; this was attributed to a decrease of MTA1-S100 calcium-binding protein A4 (S100A4) complex formation. Moreover, inhibition of tube formation in MTA1-KO MSS31 cells could not be rescued by stimulation with vascular endothelial growth factor (VEGF). These results demonstrated that MTA1 is an essential molecule for angiogenesis, and that it may be involved in different steps of the angiogenic process compared to the VEGF-VEGF receptor 2 (VEGFR2) pathway. Our findings showed that endothelial MTA1 and its pathway are promising targets for inhibiting tumor angiogenesis, supporting the development of MTA1-based anti-angiogenic therapies.

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“…As such, MTA1 siRNA inhibited tumor angiogenesis and tumor growth through the partial downregulation of S100A4 in a human pancreatic cancer xenograft model, suggesting that the MTA1-S100A4 axis is a target for cancer therapy. S100A4 also interacts with a variety of effector proteins, including the heavy chain of non-muscle myosin II-A (NMIIA), F-actin, tropomyosin, Liprin β1, the Rho-binding domain of Rhotekin, the tumor suppressor p53 and Annexin A2, through which the complex probably regulates cell motility and apoptosis (6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Inhibition Of the Invasion And Metastasis Of Mammary Carcinoma Cells By Nbd Peptide Targeting S100a4 Via The Suppression Of The mentioning

confidence: 99%

“…Furthermore, its high expression has been shown to be associated with tumor aggressiveness and poor outcomes in patients with a variety of cancers (3). Although the precise molecular mechanisms underlying the S100A4-mediated enhancement of invasion and metastasis remain to be completely elucidated, a number of studies have revealed some of these mechanisms by focusing on the discovery of effector proteins with which S100A4 interacts in a Ca 2+ -dependent manner (3)(4)(5)(6). To date, dozens of such effector proteins have been reported.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the invasion and metastasis of mammary carcinoma cells by NBD peptide targeting S100A4 via the suppression of the Sp1/MMP‑14 axis

Takenaga

Ochiya²,

Endo

2021

Int J Oncol

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A synthetic peptide that blocks the interaction between the metastasis-enhancing calcium-binding protein, S100A4, and its effector protein, methionine aminopeptidase 2 (MetAP2) (the NBD peptide), was previously demonstrated to inhibit the angiogenesis of endothelial cells, leading to the regression of human prostate cancer in a xenograft model. However, the effects of the NBD peptide on the malignant properties of cancer cells that express S100A4 remain to be elucidated. The present study demonstrates that the NBD peptide inhibits the invasiveness and metastasis of highly metastatic human mammary carcinoma cells. The introduction of the peptide into MDA-MB-231 variant cells resulted in the suppression of matrix degradation in a gelatin invadopodia assay and invasiveness in a Matrigel invasion assay. In line with these results, the peptide significantly downregulated the expression of matrix metalloproteinase (MMP)-14 (MT1-MMP). Mechanistic analysis of the downregulation of MMP-14 revealed the suppression of the expression of the transcription factor, specificity protein 1 (Sp1), but not that of nuclear factor (NF)-κB, early growth response 1 (EGR1) or ELK3, all of which were reported to be involved in transcriptional regulation of the MMP-14 gene. At the same time, evidence suggested that the NBD peptide also suppressed Sp1 and MMP-14 expression levels in MDA-MB-468 cells. Importantly, the intravenous administration of the NBD peptide encapsulated in liposomes inhibited pulmonary metastasis from mammary gland tumors in mice with xenograft tumors. These results indicate that the NBD peptide can suppress malignant tumor growth through the suppression of the Sp1/MMP-14 axis. Taken together, these results reveal that the NBD peptide acts on not only endothelial cells, but also on tumor cells in an integrated manner, suggesting that the peptide may prove to be a promising cancer therapeutic peptide drug.

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Correlation of two distinct metastasis-associated proteins, MTA1 and S100A4, in angiogenesis for promoting tumor growth

Cited by 22 publications

References 33 publications

Obesity reduces the anticancer effect of AdipoRon against orthotopic pancreatic cancer in diet-induced obese mice

Obesity reduces the anticancer effect of AdipoRon against orthotopic pancreatic cancer in diet-induced obese mice

Endothelial metastasis-associated protein 1 (MTA1) is an essential molecule for angiogenesis

Inhibition of the invasion and metastasis of mammary carcinoma cells by NBD peptide targeting S100A4 via the suppression of the Sp1/MMP‑14 axis

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