Novel Nargenicin A1 Analog Inhibits Angiogenesis by Downregulating the Endothelial VEGF/VEGFR2 Signaling and Tumoral HIF-1α/VEGF Pathway

Han, Jang Mi; Choi, Ye Seul; Dhakal, Dipesh; Sohng, Jae Kyung; Jung, Hye Jin

doi:10.3390/biomedicines8080252

Cited by 12 publications

(11 citation statements)

References 32 publications

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“…Similar to compound 9 treatment, CypA silencing reduced the expression of CD147 and the phosphorylation of JNK and ERK1/2. Furthermore, the suppressive effects of CypA silencing on the proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of HIF-1α and VEGF expression, consistent with the effects of compound 9 reported in our previous studies [ 14 , 15 ]. Taken together, our findings imply that CypA regulates CD147 expression in GC, and thus, it affects CD147-mediated downstream signaling and subsequent cellular response.…”

Section: Discussionsupporting

confidence: 90%

“…We previously found that compound 9 decreased in vitro AGS cell-induced angiogenesis of HUVECs by blocking the expression of HIF-1α and VEGF in AGS cells [ 15 ]. To assess whether CypA knockdown affects the angiogenic properties of HUVECs induced by AGS cells, conditioned medium (CM) was obtained from AGS cells and used as an angiogenic stimulus for the proliferation and invasion of HUVECs.…”

Section: Resultsmentioning

confidence: 99%

“…Further analysis of the underlying molecular mechanism of its anticancer effect demonstrated that compound 9 exhibits a growth inhibitory effect against AGS human GC cells by inducing G2/M cell cycle arrest and reactive oxygen species (ROS)- and caspase-mediated apoptosis through the downregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway [ 14 ]. More recently, we found that compound 9 exerts antiangiogenic activity via dual downregulation of vascular endothelial growth factor (VEGF)/VEGFR2-mediated signaling in human umbilical vein endothelial cells (HUVECs) and hypoxia-inducible factor-1α (HIF-1α)/VEGF expression in AGS GC cells [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells

Han

Sohng

Lee

et al. 2021

IJMS

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We recently discovered a novel nargenicin A1 analog, 23-demethyl 8,13-deoxynargenicin (compound 9), with potential anti-cancer and anti-angiogenic activities against human gastric adenocarcinoma (AGS) cells. To identify the key molecular targets of compound 9, that are responsible for its biological activities, the changes in proteome expression in AGS cells following compound 9 treatment were analyzed using two-dimensional gel electrophoresis (2-DE), followed by MALDI/TOF/MS. Analyses using chemical proteomics and western blotting revealed that compound 9 treatment significantly suppressed the expression of cyclophilin A (CypA), a member of the immunophilin family. Furthermore, compound 9 downregulated CD147-mediated mitogen-activated protein kinase (MAPK) signaling pathway, including c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase 1/2 (ERK1/2) by inhibiting the expression of CD147, the cellular receptor of CypA. Notably, the responses of AGS cells to CypA knockdown were significantly correlated with the anticancer and antiangiogenic effects of compound 9. CypA siRNAs reduced the expression of CD147 and phosphorylation of JNK and ERK1/2. In addition, the suppressive effects of CypA siRNAs on proliferation, migration, invasion, and angiogenesis induction of AGS cells were associated with G2/M cell cycle arrest, caspase-mediated apoptosis, inhibition of MMP-9 and MMP-2 expression, inactivation of PI3K/AKT/mTOR pathway, and inhibition of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression. The specific interaction between compound 9 and CypA was also confirmed using the drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA) approaches. Moreover, in silico docking analysis revealed that the structure of compound 9 was a good fit for the cyclosporin A binding cavity of CypA. Collectively, these findings provide a novel molecular basis for compound 9-mediated suppression of gastric cancer progression through the targeting of CypA.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells

Han

Sohng

Lee

et al. 2021

IJMS

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“…HIF-1α is stably expressed under hypoxia; it can regulate EPO and VEGF expression and promote RNV[ 44 , 45 ]. Inhibiting the VEGF/VEGFR2 and HIF-1α/VEGF signaling pathways can prevent angiogenesis[ 46 ]. TGF-β2 is a pro-inflammatory cytokine precursor related to the pathogenesis of DR. IGF1 has been identified as the direct target of miR-142-5p.…”

Section: Discussionmentioning

confidence: 99%

Expression and role of P-element-induced wimpy testis-interacting RNA in diabetic-retinopathy in mice

Yu¹,

Ren²,

Chen³

2021

WJD

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BACKGROUND As one of the major microvascular complications of diabetes, diabetic retinopathy (DR) is the leading cause of blindness in the working age population. Because the extremely complex pathogenesis of DR has not been fully clarified, the occurrence and development of DR is closely related to tissue ischemia and hypoxia and neovascularization The formation of retinal neovascularization (RNV) has great harm to the visual acuity of patients. AIM To investigate the expression of P-element-induced wimpy testis-interacting RNA (piRNA) in proliferative DR mice and select piRNA related to RNV. METHODS One hundred healthy C57BL/6J mice were randomly divided into a normal group as control group (CG) and proliferative DR (PDR) group as experimental group (EG), with 50 mice in each group. Samples were collected from both groups at the same time, and the lesions of mice were evaluated by hematoxylin and eosin staining and retinal blood vessel staining. The retinal tissues were collected for second-generation high-throughput sequencing, and the differentially expressed piRNA between the CG and EG was detected, and polymerase chain reaction (PCR) was conducted for verification. The differentially obtained piRNA target genes and expression profiles were enrichment analysis based on gene annotation (Gene Ontology) and Kyoto Encyclopedia of Genes and Genomes. RESULTS In the CG there was no perfusion area, neovascularization and endothelial nucleus broke through the inner boundary membrane of retinap. In the EG, there were a lot of nonperfused areas, new blood vessels and endothelial nuclei breaking through the inner boundary membrane of the retina. There was a statistically significant difference in the number of vascular endothelial nuclei breaking through the inner retinal membrane between the two groups. High-throughput sequencing analysis showed that compared with the CG, a total of 79 piRNAs were differentially expressed in EG, among which 43 piRNAs were up-regulated and 36 piRNAs were down-regulated. Bioinformatics analysis showed that the differentially expressed piRNAs were mainly concentrated in the signaling pathways of angiogenesis and cell proliferation. Ten piRNAs were selected for PCR, and the results showed that the expression of piR-MMU-40373735, piR-MMU-61121420, piR-MMU-55687822, piR-MMU-1373887 were high, and the expression of piR-MMU-7401535, piR-MMU-4773779, piR-MMU-1304999, and piR-MMU-5160126 were low, which were consistent with the sequencing results. CONCLUSION In the EG, the abnormal expression of piRNA is involved in the pathway of angiogenesis and cell proliferation, suggesting that piRNAs have some regulatory function in proliferative diabetic-retinopathy.

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“…Compound 9 is a new analog of nargenicin A1, an antibacterial macrolide with effective activity against various Gram-positive bacteria [ 83 ]. It possesses potential antitumor and antiangiogenic activity, unlike nargenicin A1 [ 83 , 99 ]. Proteomics analysis and further functional studies demonstrated that compound 9 binds to CypA and downregulates the CD147-mediated MAPK signaling pathway, including JNK and ERK1/2, by inhibiting CypA and CD147 expression in gastric cancer cells [ 13 ].…”

Section: Therapeutic Potential Of Targeting Cypa/cd147 In Cancermentioning

confidence: 99%

Cyclophilin A/CD147 Interaction: A Promising Target for Anticancer Therapy

Han

Jung

2022

IJMS

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Cyclophilin A (CypA), which has peptidyl–prolyl cis-trans isomerase (PPIase) activity, regulates multiple functions of cells by binding to its extracellular receptor CD147. The CypA/CD147 interaction plays a crucial role in the progression of several diseases, including inflammatory diseases, coronavirus infection, and cancer, by activating CD147-mediated intracellular downstream signaling pathways. Many studies have identified CypA and CD147 as potential therapeutic targets for cancer. Their overexpression promotes growth, metastasis, therapeutic resistance, and the stem-like properties of cancer cells and is related to the poor prognosis of patients with cancer. This review aims to understand the biology and interaction of CypA and CD147 and to review the roles of the CypA/CD147 interaction in cancer pathology and the therapeutic potential of targeting the CypA/CD147 axis. To validate the clinical significance of the CypA/CD147 interaction, we analyzed the expression levels of PPIA and BSG genes encoding CypA and CD147, respectively, in a wide range of tumor types using The Cancer Genome Atlas (TCGA) database. We observed a significant association between PPIA/BSG overexpression and poor prognosis, such as a low survival rate and high cancer stage, in several tumor types. Furthermore, the expression of PPIA and BSG was positively correlated in many cancers. Therefore, this review supports the hypothesis that targeting the CypA/CD147 interaction may improve treatment outcomes for patients with cancer.

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Novel Nargenicin A1 Analog Inhibits Angiogenesis by Downregulating the Endothelial VEGF/VEGFR2 Signaling and Tumoral HIF-1α/VEGF Pathway

Cited by 12 publications

References 32 publications

Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells

Identification of Cyclophilin A as a Potential Anticancer Target of Novel Nargenicin A1 Analog in AGS Gastric Cancer Cells

Expression and role of P-element-induced wimpy testis-interacting RNA in diabetic-retinopathy in mice

Cyclophilin A/CD147 Interaction: A Promising Target for Anticancer Therapy

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