Neem Leaf Glycoprotein Restrains VEGF Production by Direct Modulation of HIF1α-Linked Upstream and Downstream Cascades

Saha, Akata; Nandi, Partha; Dasgupta, Shayani; Bhuniya, Avishek; Ganguly, Nilanjan; Ghosh, Tithi; Guha, Ipsita; Banerjee, Saptak; Baral, Rathindranath; Bose, Anamika

doi:10.3389/fonc.2020.00260

Cited by 10 publications

(12 citation statements)

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“…Recent insights on molecular mechanism of NLGPmediated VEGF downregulation have revealed direct modulatory role of NLGP in inhibiting the binding of HIF1α with its cofactors CBP/p300 and Sp3, which ultimately limit VEGF transcription by preventing recruitment of HIF1α-transcriptional complex on the HIF 1α Response Element (HRE) in VEGF promoter. 15 Therefore, it is expected that modulation of HIF1α by NLGP contributes to the downregulation of TGFβ and other HIF1α target genes within TME. 14,41 Detailed mechanistic studies of RGS5 mediated apoptosis/survival in tumor-pericytes revealed that RGS5 succeed in re-establishing association with Gαi and Gαq within RGS5 + NG2 + pericytes upon NLGP treatment, which was hindered in PBS-treated B16-F10 melanoma.…”

Section: Discussionmentioning

confidence: 99%

“…Recent insights on molecular mechanism of NLGP‐mediated VEGF downregulation have revealed direct modulatory role of NLGP in inhibiting the binding of HIF1α with its cofactors CBP/p300 and Sp3, which ultimately limit VEGF transcription by preventing recruitment of HIF1α‐transcriptional complex on the HIF 1α Response Element (HRE) in VEGF promoter 15 . Therefore, it is expected that modulation of HIF1α by NLGP contributes to the downregulation of TGFβ and other HIF1α target genes within TME 14,41 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to reported bioactive anti‐tumor components of various neem preparations, 1 we have consistently reported on immunomodulatory activity of a neem component, termed Neem leaf glycoprotein (NLGP) in improving anti‐tumor immune response 2–9 . NLGP administration in murine tumor models facilitate immune cell (chiefly CD8 + T cells) infiltration, dendritic cell maturation for antigen presentation and overcome suppression from various suppressor cells at tumor site 6,10–13 NLGP significantly shifts type 2 immune polarization to type 1, 4 normalizes cytokine milieu and aberrant vasculature within tumor microenvironment (TME) 7,14 parallelly downregulating hypoxic milieu by preventing Stat3‐dependent HIF1α transcription 15 . Collectively, NLGP assists tumor restriction by strengthening host's immunity, particularly by potentiating CD8 + T cell mediated cellular immunity without direct tumor cell killing 6,16 …”

Section: Introductionmentioning

confidence: 99%

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NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

et al. 2022

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Altered RGS5‐associated intracellular pericyte signaling and its abnormal crosstalk with endothelial cells (ECs) result chaotic tumor‐vasculature, prevent effective drug delivery, promote immune‐evasion and many more to ensure ultimate tumor progression. Moreover, the frequency of lethal‐RGS5high pericytes within tumor was found to increase with disease progression, which signifies the presence of altered cell death pathway within tumor microenvironment (TME). In this study, we checked whether and how neem leaf glycoprotein (NLGP)‐immunotherapy‐mediated tumor growth restriction is associated with modification of pericytes' signaling, functions and its interaction with ECs. Analysis of pericytes isolated from tumors of NLGP treated mice suggested that NLGP treatment promotes apoptosis of NG2+RGS5high‐fuctionally altered pericytes by downregulating intra‐tumoral TGFβ, along with maintenance of more matured RGS5neg pericytes. NLGP‐mediated inhibition of TGFβ within TME rescues binding of RGS5 with Gαi and thereby termination of PI3K‐AKT mediated survival signaling by downregulating Bcl2 and initiating pJNK mediated apoptosis. Limited availability of TGFβ also prevents complex‐formation between RGS5 and Smad2 and rapid RGS5 nuclear translocation to mitigate alternate immunoregulatory functions of RGS5high tumor‐pericytes. We also observed binding of Ang1 from pericytes with Tie2 on ECs in NLGP‐treated tumor, which support re‐association of pericytes with endothelium and subsequent vessel stabilization. Furthermore, NLGP‐therapy‐ associated RGS5 deficiency relieved CD4+ and CD8+ T cells from anergy by regulating ‘alternate‐APC‐like’ immunomodulatory characters of tumor‐pericytes. Taken together, present study described the mechanisms of NLGP's effectiveness in normalizing tumor‐vasculature by chiefly modulating pericyte‐biology and EC‐pericyte interactions in tumor‐host to further strengthen its translational potential as single modality treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

et al. 2022

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“…Although several ginsenosides active components of ginseng, including Rb1, Rg3, and Rd served as tumor angiogenesis inhibitors ( Li et al, 2021b ), it is noteworthy that the angiogenic modulation of the rest of the ginsenosides, containing protopanaxadiols, protopanaxatriols, and oleanane types ( Zhou et al, 2022 ), were incompletely investigated. In addition, neem leaf glycoprotein (NLGP), a natural immune-modulator obtained from the leaves of neem ( Azadirachta indica A. juss), balked M2 polarization of TAMs and HIF1α/VEGF signaling with STAT3-dependent manner and induced tumor vessel normalization with CD8 + T cells dependence by downmodulating VEGF and VEGFR2 ( Banerjee et al, 2014 ; Goswami et al, 2014 ; Saha et al, 2020 ). As a part of the anti-tumor mechanism of legume lectin proteins, its anti-angiogenesis effect has been reported that Dolichos lablab L. lectin (DLL) protein weakened the expression of pro-angiogenic factors encompassing NF-κB, HIF-1 α, MMP-2 and 9, and VEGF, while the concanavalin A exhibited anti-angiogenic action via targeting IKK-NF-κB-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK cascade ( Li et al, 2011 ; Vigneshwaran et al, 2017 ).…”

Section: The Role Of Ethnopharmacology In Tumor Angiogenesismentioning

confidence: 99%

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

et al. 2022

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Tumor angiogenesis is one of the most important processes of cancer deterioration via nurturing an immunosuppressive tumor environment (TME). Targeting tumor angiogenesis has been widely accepted as a cancer intervention approach, which is also synergistically associated with immune therapy. However, drug resistance is the biggest challenge of anti-angiogenesis therapy, which affects the outcomes of anti-angiogeneic agents, and even combined with immunotherapy. Here, emerging targets and representative candidate molecules from ethnopharmacology (including traditional Chinese medicine, TCM) have been focused, and they have been proved to regulate tumor angiogenesis. Further investigations on derivatives and delivery systems of these molecules will provide a comprehensive landscape in preclinical studies. More importantly, the molecule library of ethnopharmacology meets the viability for targeting angiogenesis and TME simultaneously, which is attributed to the pleiotropy of pro-angiogenic factors (such as VEGF) toward cancer cells, endothelial cells, and immune cells. We primarily shed light on the potentiality of ethnopharmacology against tumor angiogenesis, particularly TCM. More research studies concerning the crosstalk between angiogenesis and TME remodeling from the perspective of botanical medicine are awaited.

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“…Angiogenesis is the physiological process of new blood vessel formation by endothelial cells. Many different growth factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and matrix metalloproteinases (MMPs), are known to promote angiogenesis by endothelial cells ( 1 ). Under normal conditions, angiogenesis plays an important role in a wide range of physiological processes, such as wound healing and fetal development.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Trichostatin A Reduces Endothelial Cell Proliferation by Suppressing STAT5A-Related Gene Transcription

Zhao

Peng

et al. 2021

Front. Oncol.

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Inhibitors of histone deacetylases (HDACi) have shown promising effects in preclinical applications for the treatment of many diseases. Confusedly though, the effects of the HDACi trichostatin A (TSA) on angiogenesis are variable among different diseases. This study investigated the direct effects of TSA on endothelial cells, which plays essential roles in angiogenesis and the underlying molecular events. TSA reduced the viability of human umbilical vein endothelial cells (HUVECs), in which proliferation-related genes including BIRC5, CKS1B, and NDC80 were found to be involved. Furthermore, signal transducer and activator of transcription 5 A (STAT5A) was demonstrated to be reduced by TSA and to mediate TSA-induced downregulation of BIRC5, CKS1B, and NDC80 and HUVEC proliferation. Mechanistically, data showed that STAT5A directly bound to the promoters of BIRC5, CKS1B, and NDC80 and activated their transcription through special DNA sequence sites. Finally, the TSA–STAT5A–BIRC5, CKS1B, and NDC80 axis also worked in a cancerous endothelial cell angiogenesis model. The results of this study revealed novel mechanisms underlying the effects of TSA on endothelial cells and provided insights for angiogenesis-associated diseases.

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Neem Leaf Glycoprotein Restrains VEGF Production by Direct Modulation of HIF1α-Linked Upstream and Downstream Cascades

Cited by 10 publications

References 50 publications

NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

NLGP regulates RGS5‐TGFβ axis to promote pericyte‐dependent vascular normalization during restricted tumor growth

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

Histone Deacetylase Inhibitor Trichostatin A Reduces Endothelial Cell Proliferation by Suppressing STAT5A-Related Gene Transcription

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