Apoptosis Induced by (+)-Betulin Through NF-κB Inhibition in MDA-MB-231 Breast Cancer Cells

Anaya-Eugenio, Gerardo D.; Eggers, Nicole A; Ren, Yulin; Rivera‐Chávez, José; Kinghorn, A. Douglas; Blanco, Esperanza J. Carcache de

doi:10.21873/anticanres.14688

Cited by 17 publications

(23 citation statements)

References 23 publications

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“…Our results show very high expression levels of p-NF-kB/p65 in tumors derived from SMAC expressing A549 cells that were highly reduced in tumors lacking SMAC. This decrease in p-NF-kB/p65 can induce apoptosis as found in other studies where apoptosis was induced when NF-kB activation was inhibited by different means ( 61 , 62 ).…”

Section: Discussionsupporting

confidence: 83%

“…Our results show very high expression levels of the activated p-NF-kB/p65 in tumors derived from SMAC-expressing A549 cells, that was highly reduced (over 90%) in SMAC-lacking tumors. This decrease in p-NF-kB/p65 led to reduced inflammation ( Figure 6 ) and apoptosis ( Figure 3 ), as also obtained when NF-kB activation was induced by different means ( 61 , 62 ).…”

Section: Discussionsupporting

confidence: 74%

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Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression

et al. 2022

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Mitochondrial SMAC/Diablo induces apoptosis by binding the inhibitor of apoptosis proteins (IAPs), thereby activating caspases and, subsequently, apoptosis. Previously, we found that despite its pro-apoptotic activity, SMAC/Diablo is overexpressed in cancer, and demonstrated that in cancer it possesses new essential and non-apoptotic functions that are associated with regulating phospholipid synthesis including modulating mitochondrial phosphatidylserine decarboxylase activity. Here, we demonstrate additional functions for SMAC/Diablo associated with inflammation and immunity. CRISPR/Cas9 SMAC/Diablo-depleted A549 lung cancer cells displayed inhibited cell proliferation and migration. Proteomics analysis of these cells revealed altered expression of proteins associated with lipids synthesis and signaling, vesicular transport and trafficking, metabolism, epigenetics, the extracellular matrix, cell signaling, and neutrophil-mediated immunity. SMAC-KO A549 cell-showed inhibited tumor growth and proliferation and activated apoptosis. The small SMAC-depleted “tumor” showed a morphology of alveoli-like structures, reversed epithelial-mesenchymal transition, and altered tumor microenvironment. The SMAC-lacking tumor showed reduced expression of inflammation-related proteins such as NF-kB and TNF-α, and of the PD-L1, associated with immune system suppression. These results suggest that SMAC is involved in multiple processes that are essential for tumor growth and progression. Thus, targeting SMAC’s non-canonical function is a potential strategy to treat cancer.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 74%

Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression

et al. 2022

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“…For corymboside, there are no in vitro and in vivo studies regarding its efficacy on cancer cells. According to Anaya-Eugenio et al [ 16 ], betulin is a pentacyclic triterpenoid compound that inhibits the growth of MDA-MB-231 cells downregulating NF- κ B p65 expression in silico and in vitro. In vitro experiment by Seo et al [ 17 ] also confirmed that apigenin could decrease the colony formation of MCF-7 cells by downregulating the STAT3 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Comparative Study of Antiproliferative Activity in Different Plant Parts of Phaleria macrocarpa and the Underlying Mechanism of Action

Christina

Rifa’i

Widodo

et al. 2022

The Scientific World Journal

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Phaleria macrocarpa is a medicinal plant widely used in Indonesian folk medicine to treat several diseases, including cancer. However, the comparative evaluation of various plant parts of P. macrocarpa has not been studied for their anticancer properties on breast cancer. The study aimed to assess the antiproliferative activity of the ethanol extract of various parts of Phaleria macrocarpa against T47D human breast cancer cell lines. Several parts of P. macrocarpa, including pericarp, mesocarp, seed, and leaf, were used to determine the most potent plant part to inhibit the growth of T47D cells. The cytotoxic effects of each plant part were evaluated by WST-1 assay. The apoptotic level of T47D cells was determined by annexin V-FITC-PI and DNA fragmentation assay. Propidium iodide staining and the CFSE assay were used to examine the effect of each extract on cell cycle distribution and cell division, respectively. The relative number of caspase-3, Bax, and Bcl-2 was analyzed by flow cytometry technique. WST-1 assay revealed that P. macrocarpa leaves exhibited the most potent antiproliferative activity ( p < 0.05 ) compared to other plant parts with selectivity only to T47D cells. P. macrocarpa leaves extract effectively induced apoptosis, inhibited proliferation, and arrested the cell cycle of T47D cells. The relative number of caspase-3 was significantly ( p < 0.05 ) increased after being treated with P. macrocarpa leaf extract. P. macrocarpa leaf extract also leads to the dose-dependent accumulation in the Bax/Bcl-2 ratio due to upregulation of Bax and downregulation of Bcl-2. The overall results indicated that P. macrocarpa leaves could inhibit the proliferation of T47D cells and trigger apoptosis through caspase-3 activation and Bax/Bcl regulation. Therefore, P. macrocarpa leaves can be used for breast cancer therapy.

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“…Unless otherwise indicated, the cells were stimulated by recombinant human (rh) TNFα (50 ng/mL; #300-01A, PeproTech, Rocky Hill, NJ, USA), rhIL-1β (500 pg/mL, #200-01B, PeproTech) and/or rhIFNγ (20 ng/mL, #300-02B, PeproTech). The cytokine concentrations were selected based on titration analyses that were performed beforehand, and they agree with the conventional dose range used in other research systems (TNFα: [ 67 , 68 , 69 ]; IL-1β: [ 70 , 71 , 72 ]; IFNγ: [ 73 , 74 ]). In all procedures, control non-stimulated cells were treated with the vehicle of the stimulating cytokines (0.1% BSA diluted in double distilled water).…”

Section: Methodsmentioning

confidence: 99%

Inflammation-Driven Regulation of PD-L1 and PD-L2, and Their Cross-Interactions with Protective Soluble TNFα Receptors in Human Triple-Negative Breast Cancer

Baram

Oren

Erlichman

et al. 2022

Cancers

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Pro-inflammatory cytokines play key roles in elevating cancer progression in triple-negative breast cancer (TNBC). We demonstrate that specific combinations between TNFα, IL-1β and IFNγ up-regulfated the proportion of human TNBC cells co-expressing the inhibitory immune checkpoints PD-L1 and PD-L2: TNFα + IL-1β in MDA-MB-231 cells and IFNγ + IL-1β in BT-549 cells; in the latter cells, the process depended entirely on STAT1 activation, with no involvement of p65 (CRISPR-Cas9 experiments). Highly significant associations between the pro-inflammatory cytokines and PD-L1/PD-L2 expression were revealed in the TCGA dataset of basal-like breast cancer patients. In parallel, we found that the pro-inflammatory cytokines regulated the expression of the soluble receptors of tumor necrosis factor α (TNFα), namely sTNFR1 and sTNFR2; moreover, we revealed that sTNFR1 and sTNFR2 serve as anti-metastatic and protective factors in TNBC, reducing the TNFα-induced production of inflammatory pro-metastatic chemokines (CXCL8, CXCL1, CCL5) by TNBC cells. Importantly, we found that in the context of inflammatory stimulation and also without exposure to pro-inflammatory cytokines, elevated levels of PD-L1 have down-regulated the production of anti-tumor sTNFR1 and sTNFR2. These findings suggest that in addition to its immune-suppressive activities, PD-L1 may promote disease course in TNBC by inhibiting the protective effects of sTNFR1 and sTNFR2.

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Apoptosis Induced by (+)-Betulin Through NF-κB Inhibition in MDA-MB-231 Breast Cancer Cells

Cited by 17 publications

References 23 publications

Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression

Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression

Comparative Study of Antiproliferative Activity in Different Plant Parts of Phaleria macrocarpa and the Underlying Mechanism of Action

Inflammation-Driven Regulation of PD-L1 and PD-L2, and Their Cross-Interactions with Protective Soluble TNFα Receptors in Human Triple-Negative Breast Cancer

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