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Increased FOXA1 levels induce apoptosis and inhibit proliferation in FOXA1-low expressing basal breast cancer cells.

ABSTRACT: The transcription factor FOXA1, which is a member of the forkhead class of DNA-binding proteins, interacts with Estrogen Receptor (ER) to mediate breast cancer progression. However, its role in basal breast cancer cells remains unclear. Although the overall levels of FOXA1 are decreased in the basal subtype of clinical TCGA breast cancer samples, the high levels of FOXA1 improve the survival of the patients from this subtype. This clinical phenomenon is consistent with that of FOXA1 stimulating apoptosis in FOXA1-low expressing basal breast cancer cells, such as MDA-MB-231, and MDA-MB-468 cells. In this study, we have constructed an inducible expression system of FOXA1 and demonstrated the induced expression of FOXA1 resulting in apoptosis and cell cycle arrest in MDA-MB-231 cells, as confirmed by transcriptomic analysis and in vivo tumor-grafted models. Furthermore, the low levels of Estrogen Receptor-1 (ESR1) are critical for FOXA1 in terms of its repressive roles in the cells, as evidenced by clinical data analysis indicating that the high levels of FOXA1 improve the survival of ESR1^Low patients, but worsen the survival of ESR1^High patients of breast cancer. When introduced into MDA-MB-231 cells, ESR1 counteracts the tumor suppressor roles of FOXA1 by altering the FOXA1-regulated gene transcription and the two proteins together maintain the tumor progression in vivo. Our cumulative results suggest that FOXA1 suppresses the basal breast cancer cells with FOXA1-low expressing status independent of ESR1 by inducing apoptosis and inhibiting cell proliferation, thereby implicating its potential therapeutic role in this group of breast cancer.

SUBMITTER: Xia K

PROVIDER: S-EPMC9251680 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Artemisia Capillaris leaves inhibit cell proliferation and induce apoptosis in hepatocellular carcinoma.

Project description:BACKGROUND:Natural product is one of the most important sources of drugs used in pharmaceutical therapeutics. Artemisia capillaris has been traditionally used as a hepatoprotective and anti-inflammatory agent. In this study, we extracted an ethanol fraction (LAC117) from the dried leaves of Artemisia capillaris and identified its anticancer activity and mechanism of action against hepatocellular carcinoma (HCC). METHODS:Anti-proliferative effect of LAC117 was evaluated by MTT assay and BrdU assay. The apoptotic effect of LAC117 on the expression of cleaved PARP and cleaved caspase-3 was evaluated by Western blot and immunohistochemistry from in vivo mouse xenograft, respectively. RESULTS:We found that LAC117 strongly suppressed the growth and proliferation of human HCC cell lines (HepG2 and Huh7). Induction of apoptosis was evidenced by the increases of cleaved caspase-3 and PARP as well as TUNEL-positive cells. Additionally, the pro-apoptotic effect of LAC117 was observed by a decrease in the expression of the XIAP and an increase in cytochrome c releases via mitochondrial membrane potential. Moreover, it significantly inhibited PI3K/AKT pathway in HCC in vivo and in vitro. LAC117 suppressed tumor growth in an ex vivo model as well as in vivo mouse xenograft by inducing apoptosis and inhibiting tumor cell proliferation. CONCLUSIONS:The present study highlights that LAC117 could not only efficiently induce apoptosis, but also inhibit the growth of human HCC cells by blocking the PI3K/AKT signaling pathway, suggesting that LAC117 would be a potentially useful drug candidate against HCC.

| S-EPMC5941330 | biostudies-literature

Statins inhibit proliferation and induce apoptosis in triple-negative breast cancer cells.

Project description:TP53 (p53) is mutated in 80-90% of cases of triple-negative breast cancer (TNBC). Statins, which are widely used to treat elevated cholesterol, have recently been shown to degrade mutant p53 protein and exhibit anti-cancer activity. The aim of this work was to evaluate the potential of statins in the treatment of TNBC. The anti-proliferative effects of 2 widely used statins were investigated on a panel of 15 cell lines representing the different molecular subtypes of breast cancer. Significantly lower IC50 values were found in triple-negative (TN) than in non-TN cell lines (atorvastatin, p < 0.01; simvastatin p < 0.05) indicating greater sensitivity. Furthermore, cell lines containing mutant p53 were more responsive to both statins than cell lines expressing wild-type p53, suggesting that the mutational status of p53 is a potential predictive biomarker for statin response. In addition to inhibiting proliferation, simvastatin was also found to promote cell cycle arrest and induce apoptosis. Using an apoptosis array capable of detecting 43 apoptosis-associated proteins, a novel protein shown to be upregulated by simvastatin was the IGF-signalling modulator, IGBP4, a finding we confirmed by Western blotting. Finally, we found synergistic growth inhibition between simvastatin and the IGF-1R inhibitor, OSI-906 as well as between simvastatin and doxorubicin or docetaxel. Our work suggests repurposing of statins for clinical trials in patients with TNBC. Based on our findings, we suggest that these trials investigate statins in combination with either doxorubicin or docetaxel and include p53 mutational status as a potential predictive biomarker.

| S-EPMC9283343 | biostudies-literature

Garlic (Allium sativum)-derived SEVs inhibit cancer cell proliferation and induce caspase mediated apoptosis.

Project description:As a key component of the cell-to-cell communication, small extracellular vesicles (SEVs) released from various sources are known to be affecting the physiological conditions of the target cells. Although it has been suggested that edible plant-derived nanoparticles contributes to the cross kingdom communication with the mammalian cells, the effect of these particles on cancer cell progression still needs a further exploration. Here, we isolated and then characterized garlic derived SEVs by nanoparticle tracking analysis, electron microscopy and SEV surface antibodies. In order to investigate anti-cancer property of garlic SEVs A498 human kidney carcinoma, A549 human lung carcinoma were used as cell models along with the normal human dermal fibroblast cell lines. Annexin V/pI staining and analysis of apoptotic mRNA and protein expression levels suggested that garlic SEVs induced apoptosis through activation of intrinsic pathway. Furthermore, angiogenic VEGF protein expression levels significantly decreased in response to SEVs treatment in cancer cells. Our results support that garlic derived SEVs could cause apoptotic cell death among cancer cells while normal cells remain unaffected with the treatment. This study revealed for the first time that plant SEVs possess anti-cancer affects by inducing caspase mediated apoptosis and provided a new alternative for cancer treatment.

| S-EPMC8292337 | biostudies-literature

Gastric cancer cells inhibit natural killer cell proliferation and induce apoptosis via prostaglandin E2.

Project description:Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we showed, in detailed studies of NK cells from 235 untreated patients with gastric cancer (GC), the NK cell density in GC tissues could predict improved survival of patients. However, NK cells were significantly decreased in number with advanced-stage GC. A multivariate Cox analysis revealed that the intratumoral NK cell density was an independent prognostic factor for overall survival and disease-free survival in the GC patients. Most of the intratumoral NK cells exhibited a normal phenotype and secreted normal levels of cytokines, but the expression of Ki67 was decreased compared with NK cells from nontumoral regions. Moreover, the levels of intratumoral NK cells were negatively correlated with the intratumoral expression of cyclooxygenase-2. Furthermore, we found that PGE2 derived from GC cells suppressed NK cell proliferation and increased apoptosis in vitro. These data reveal that tumor-derived PGE2 is critical for inducing NK cell dysfunction in GC and demonstrate that an extensive infiltration of NK cells predicts a good prognosis in patients with GC. Our findings suggest that immunosuppressive barriers erected by tumors greatly hamper the antitumor activity of human NK cells, thereby favoring tumor outgrowth and progression.

| S-EPMC4801461 | biostudies-literature

Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation.

Project description:Aging is associated with progressive telomere shortening, resulting in the formation of dysfunctional telomeres that compromise tissue proliferation. However, dysfunctional telomeres can limit tumorigenesis by activating p53-dependent cellular senescence and apoptosis. While activation of both senescence and apoptosis is required for repress tumor formation, it is not clear which pathway is the major tumor suppressive pathway in vivo. In this study, we generated E?-myc; Pot1b(?/?) mouse to directly compare tumor formation under conditions in which either p53-dependent apoptosis or senescence is activated by telomeres devoid of the shelterin component Pot1b. We found that activation of p53-dependent apoptosis plays a more critical role in suppressing lymphoma formation than p53-dependent senescence. In addition, we found that telomeres in Pot1b(?/?) ; p53(-/-) mice activate an ATR-Chk1-dependent DNA damage response to initiate a robust p53-independent, p73-dependent apoptotic pathway that limited stem cell proliferation but suppressed B-cell lymphomagenesis. Our results demonstrate that in mouse models, both p53-dependent and p53-independent apoptosis are important to suppressing tumor formation.

| S-EPMC4933665 | biostudies-literature

New castanospermine glycoside analogues inhibit breast cancer cell proliferation and induce apoptosis without affecting normal cells.

Project description:sp²-Iminosugar-type castanospermine analogues have been shown to exhibit anti-tumor activity. However, their effects on cell proliferation and apoptosis and the molecular mechanism at play are not fully understood. Here, we investigated the effect of two representatives, namely the pseudo-S- and C-octyl glycoside 2-oxa-3-oxocastanospermine derivatives SO-OCS and CO-OCS, on MCF-7 and MDA-MB-231 breast cancer and MCF-10A mammary normal cell lines. We found that SO-OCS and CO-OCS inhibited breast cancer cell viability in a concentration- and time-dependent manner. This effect is specific to breast cancer cells as both molecules had no impact on normal MCF-10A cell proliferation. Both drugs induced a cell cycle arrest. CO-OCS arrested cell cycle at G1 and G2/M in MCF-7 and MDA-MB-231 cells respectively. In MCF-7 cells, the G1 arrest is associated with a reduction of CDK4 (cyclin-dependent kinase 4), cyclin D1 and cyclin E expression, pRb phosphorylation, and an overexpression of p21(Waf1/Cip1). In MDA-MB-231 cells, CO-OCS reduced CDK1 but not cyclin B1 expression. SO-OCS accumulated cells in G2/M in both cell lines and this blockade was accompanied by a decrease of CDK1, but not cyclin B1 expression. Furthermore, both drugs induced apoptosis as demonstrated by the increased percentage of annexin V positive cells and Bax/Bcl-2 ratio. Interestingly, in normal MCF-10A cells the two drugs failed to modify cell proliferation, cell cycle progression, cyclins, or CDKs expression. These results demonstrate that the effect of CO-OCS and SO-OCS is triggered by both cell cycle arrest and apoptosis, suggesting that these castanospermine analogues may constitute potential anti-cancer agents against breast cancer.

| S-EPMC3790671 | biostudies-literature

JAC1 targets YY1 mediated JWA/p38 MAPK signaling to inhibit proliferation and induce apoptosis in TNBC.

Project description:Triple negative breast cancer (TNBC) is a type of breast cancer with poor prognosis, and has no ideal therapeutic target and ideal medicine. Downregulation of JWA is closely related to the poor overall survival in many cancers including TNBC. In this study, we reported at the first time that JWA gene activating compound 1 (JAC1) inhibited the proliferation of TNBC in vitro and in vivo experimental models. JAC1 specifically bound to YY1 and eliminated its transcriptional inhibition of JWA gene. The rescued JWA induced G1 phase arrest and apoptosis in TNBC cells through the p38 MAPK signaling pathway. JAC1 also promoted ubiquitination and degradation of YY1. In addition, JAC1 disrupted the interaction between YY1 and HSF1, and suppressed the oncogenic role of HSF1 in TNBC through p-Akt signaling pathway. In conclusion, JAC1 suppressed the proliferation of TNBC through the JWA/P38 MAPK signaling and YY1/HSF1/p-Akt signaling. JAC1 maybe a potential therapeutic agent for TNBC.

| S-EPMC8983694 | biostudies-literature

Reprogramming factors induce proliferation and inhibit apoptosis of melanoma cells by changing the expression of particular genes.

Project description:Uncontrolled proliferation and defective apoptosis are two major factors responsible for maintaining the malignant properties of melanoma cells. Our previous study demonstrated that induced expression of four reprogramming factors remodeled the phenotype of B16‑F10 mouse melanoma cells into melanoma stem cells. The present study was conducted to investigate the effect of the four Yamanaka reprogramming factors, namely Oct4, Sox2, Klf4 and c‑Myc (OSKM), on the proliferation and apoptosis of melanoma cells, and to identify the responsible molecular signals. The results identified that expression of the four reprogramming factors was highly induced by doxycycline treatment in the stable melanoma cell clone that was transfected with a plasmid expressing these factors, driven by the Tet‑On element. It was further confirmed that induced expression of these factors enhanced the proliferation and suppressed the apoptosis of the melanoma cells. In addition, induced OSKM expression increased cell proliferation, accelerated the progression of the cell cycle, and upregulated the mRNA expression levels of Janus kinase 2 (JAK2) and Cyclin‑B1. Induced expression of these factors also decreased the apoptosis, as well as upregulated B‑cell lymphoma 2 (BCL‑2) and downregulated BCL‑2‑associated X (BAX) mRNA expression levels. Taken together, the results suggested that upregulated JAK2 and Cyclin‑B1 may be responsible for the enhanced proliferation of melanoma cells, and that BCL‑2 upregulation and BAX downregulation may account for the suppressed apoptosis of these cells.

| S-EPMC6323216 | biostudies-literature

FOXA1 Promotes Cell Proliferation and Suppresses Apoptosis in HCC by Directly Regulating miR-212-3p/FOXA1/AGR2 Signaling Pathway.

Project description:Background:Forkhead box protein A1 (FOXA1), acting as a transcriptional activator for liver-specific transcripts, plays a vital part in proliferation, apoptosis and cell cycle. Methods:The mRNA expression of FOXA1 in 90 HCC tissues and matched adjacent non-tumor tissues was determined by qRT-PCR. The downstream and upstream regulators of FOXA1 were identified by bioinformatics analysis and experimental confirmation. Results:We found out that the expression of FOXA1 was obviously higher in hepatocellular carcinoma (HCC) tissues than that in matched non-tumor tissues. Similarly, FOXA1 is also highly expressed in HCC cell lines as compared with normal human hepatic cell line L02. Clinical association analysis indicated that high expression of FOXA1 was prominently correlated with high HBV level, large tumor size, high venous infiltration, high Edmondson-Steiner grading, and advanced tumor-node-metastasis tumor stage. Furthermore, the in vitro tests showed that ectopic expression of FOXA1 promoted HepG2 cell proliferation and suppressed apoptosis. In contrast, the downregulation of FOXA1 inhibited cell proliferation, and induced apoptosis in Hep3B cells. To investigate the functional mechanism of FOXA1, anterior gradient 2 (AGR2), an executor in proliferation and apoptosis, was identified as the direct target gene of FOXA1. Meanwhile, we also found the expression of FOXA1 could be inhibited by miR-212-3p, which working as a tumor suppressor downregulated in HCC. Conclusion:We revealed that FOXA1 exerted its biological function by regulating AGR2 expression, and its ectopic expression may be blamed for low expression of miR-212-3p.

| S-EPMC7293390 | biostudies-literature

Increased TCP11 gene expression can inhibit the proliferation, migration and promote apoptosis of cervical cancer cells.

Project description:BackgroundCervical cancer is a common gynecological malignancy. Gene microarray found that TCP11 gene was highly expressed in cervical cancer. However, the effect of TCP11 gene on the proliferation, apoptosis and migration of cervical cancer cells and its underlying molecular mechanisms are unclear.MethodsGEPIA database, tissue microarray, western blot and qRT-PCR were used to analyze the expression of TCP11 gene in cervical cancer tissues and cells and its relationship with patients' survival rate. The cell cycle and apoptosis were detected by flow cytometry, and the expressions of cell cycle and apoptosis related molecules and EMT-related molecules were detected by Western blot and qRT-PCR.ResultsThe results showed that TCP11 gene was highly expressed in cervical cancer tissues and cells compared with normal cervical tissues and cells, and its expression was positively correlated with patients' survival rate. The results of proliferation and migration assays showed that TCP11 overexpression inhibited the proliferation and migration of HeLa and SiHa cells. The results showed that TCP11 overexpression blocked the cell cycle of HeLa and SiHa cells, decreased the expression of CDK1 and Cyclin B1, and increased the apoptosis and the expression of caspase-3, cleaved-caspase-3 and cleaved-PARP. TCP11 overexpression increased the protein and mRNA expression of EMT-related molecules ZO-1 and E-cadherin. Conversely, TCP11 knockdown promoted the proliferation of HeLa and SiHa cells and the migration of HeLa cells.ConclusionsTCP11 overexpression significantly inhibited the occurrence and development of cervical cancer cells, it may be a potentially beneficial biomarker for cervical cancer.

| S-EPMC10496356 | biostudies-literature

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