Artematrolide A inhibited cervical cancer cell proliferation via ROS/ERK/mTOR pathway and metabolic shift

BackgroundArtematrolide A (AR-A), a guaianolide dimer isolated from Artemisia atrovirens, demonstrated significant inhibitory effect on three human hepatoma cell lines (HepG2, Huh7 and SMMC7721). The anti-cervical cancer effect and mechanism of this compound have yet to be explored. This study is to reveal the role and mechanisms of artematrolide A on cervical cancer cells, and provide the pharmacological understanding of artematrolide A.PurposeTo investigate the function and possible mechanism of artematrolide A on cervical cancer cells in vitro.MethodsHeLa S3 and SiHa cells were treated with artematrolide A at various concentrations. In this study, MTT, colony formation, cell migration and invasion, cell cycle analysis, cell apoptosis, reactive oxygen species (ROS) detection, western blotting, enzyme activity, and lactate production of artematrolide A were evaluated.ResultsArtematrolide A inhibited cell viability, proliferation, migration and invasion in a dose-dependent manner, caused cell cycle arrest in G2/M phase, and induced cell apoptosis via Bcl-2/PARP-1. The mechanism of action of artematrolide A included two aspects: artematrolide A suppressed cell proliferation by activating ROS/ERK/mTOR signaling pathway and promoted glucose metabolism from aerobic glycolysis to mitochondrial respiration by activating pyruvate dehydrogenase complex (PDC) and oxoglutarate dehydrogenase complex (OGDC) via inhibiting the activity of alkaline phosphatases (ALP).ConclusionArtematrolide A exhibited a significant cytotoxic activity on cervical cancer cells, induced G2/M cell cycle arrest and apoptosis by activating ROS/ERK/mTOR signaling pathway and promoting metabolic shift from aerobic glycolysis to mitochondrial respiration, which suggested artematrolide A might be a potential agent for the treatment of cervical cancer.     

Daidzin inhibits growth and induces apoptosis through the JAK2/STAT3 in human cervical cancer HeLa cells

Daidzin, 4′, 7-dihydroxyisoflavone is an isoflavonic phytoestrogen present in leguminous plants. Traditional Chinese medicine utilizes daidzin to treat various diseases such diarrhea, fever, hepatitis, cardiac problems etc. In current study we examined the anticancer activity of daidzin against human cervical cancer in vitro. HeLa, human cervical cancer cell line was purchased from ATCC and the cells were cultured with DMEM medium. The cytotoxic effect of daidzin against HeLa cell line was analyzed with MTT assay. The IC-50 value was obtained at 20 µM hence the cells were treated with 20 µM of daidzin for further analysis. ROS generation was assessed with DCFH-DA staining and the induction of apoptosis was examined with Rhoadmine-123 staining. Acridine orange and ethidium bromide staining was done to examine the apoptotic and viable cells. Further the matrigel cell adhesion assay was done to analyze the inhibitory property of daidzin against cancer cell adhesion. Apoptotic induction of daidzin was examined by estimating the levels of Caspase 8 & 9 using ELISA technique. Inflammatory and cell proliferation signaling proteins were analyzed with qPCR analysis to confirm the anticancer activity of daidzin against human cervical cancer HeLa cell line. Daidzin significantly generated ROS and altered the mitochondrial membrane permeability in HeLa cell line. The results of AO/EtBr staining prove daidzin induced apoptosis in HeLa cell line and it also inhibited the cell adhesion property of HeLa which is reported in our matrigel cell adhesion assay. It also increased the caspases 8 & 9 which are key regulators of apoptosis. Daidzin significantly decreased the expression of inflammatory gene and cell proliferating signaling molecule. To, conclude our results confirm daidzin effectively decreased inflammation and induced apoptosis in human cervical cancer HeLa cell line.     

Downregulation of long noncoding RNA DGCR5 contributes to the proliferation,migration, and invasion of cervical cancer by activating Wnt signaling pathway

Accumulating research works have reported that long noncoding RNAs (lncRNAs) are involved in various cancers, including cervical cancer. LncRNA DGCR5 has been identified in many cancers. However, the biological role of DGCR5 in cervical cancer remains barely known. We aimed to investigate the biological function of DGCR5 in cervical cancer progression. Here, in our current study, we observed that DGCR5 was downregulated in human cervical cancer cell lines (MS751, SiHa, HeLa, and HT-3) compared with the primary normal cervical squamous cells (NCSC1 and NCSC2). Then, DGCR5 was restrained by transfection with lenti-virus-short hairpin RNA (LV-shRNA) while induced by LV-DGCR5 in HeLa and C33A cells. Silence of DGCR5 obviously induced cervical cancer cell viability and cell proliferation. Reversely, upregulation of DGCR5 inhibited HeLa and C33A cell survival and proliferation. Furthermore, silencing of DGCR5 increased cervical cancer cell colony formation ability and decreased cell apoptosis, whereas its overexpression exhibited an opposite process. Moreover, DGCR5 suppressed migration and invasion capacity of cervical cancer cells. The Wnt signaling is integral in numerous biological processes. Here, we found that Wnt signaling was strongly activated in cervical cancer cells. Downregulation of DGCR5 contributed to cervical cancer progression by activating Wnt signaling. Subsequently, in vivo animal models were used to confirm that DGCR5 suppressed cervical cancer via targeting Wnt signaling. In conclusion, we reported that DGCR5 was involved in cervical cancer progression via modulating the Wnt pathway.     

α-Mangostin attenuates stemness and enhances cisplatin-induced cell death in cervical cancer stem-like cells through induction of mitochondrial-mediated apoptosis

Cancer stem cells (CSCs) exhibit specific characteristics including decontrolled self-renewal, tumor-initiating, promoting, and metastatic potential, abnormal stemness signaling, and chemotherapy resistance. Thus, targeting CSC is becoming an emerging cancer treatment. α-Mangostin has been shown to have potent and multiple anticancer activities. Accordingly, we hypothesized that α-mangostin may diminish the stemness and proliferation of CSC-like cervical cancer cells. In our results, comparing to the parent cells, CSC-like SiHa and HeLa cells highly expressed CSC marker Sox2, Oct4, Nanog, CK-17, and CD49f. α-Mangostin significantly reduced the cell viability, sphere-forming ability, and expression of the CSC stemness makers of CSC-like cervical cancer cells. Further investigation showed that α-mangostin induced mitochondrial depolarization and mitochondrial apoptosis signaling, including upregulation of Bax, downregulation of Mcl-1 and Bcl-2, and activation of caspase-9/3. Moreover, α-mangostin synergically enhanced the cytotoxicity of cisplatin on CSC-like SiHa cells by promoting mitochondrial apoptosis and inhibiting the expression of CSC markers. Consistent with in vitro findings, in vivo tumor growth assay revealed that α-mangostin administration significantly inhibited the growth of inoculated CSC-like SiHa cells and synergically enhanced the antitumor effect of cisplatin. Our findings indicate that α-mangostin can reduce the stemness and proliferation of CSC-like SiHa and HeLa cells and promote the cytotoxicity of cisplatin, which may attribute to the mitochondrial apoptosis activation. Thus, it suggests that α-mangostin may have clinical potential to improve chemotherapy for cervical cancer by targeting cervical CSC.     

Proteomic exploration of the impacts of pomegranate fruit juice on the global gene expression of prostate cancer cell

Prostate cancer has been known to be the second highest cause of death in cancer among men. Pomegranate is rich in polyphenols with the potent antioxidant activity and inhibits cell proliferation, invasion, and promotes apoptosis in various cancer cells. This study demonstrated that pomegranate fruit juice could effectively hinder the proliferation of human prostate cancer DU145 cell. The results of apoptotic analyses implicated that fruit juice might trigger the apoptosis in DU145 cells via death receptor signaling and mitochondrial damage pathway. In this study, we exploited 2DE‐based proteomics to compare nine pairs of the proteome maps collected from untreated and treated DU145 cells to identify the differentially expressed proteins. Comparative proteomics indicated that 11 proteins were deregulated in affected DU145 cells with three upregulated and eight downregulated proteins. These dys‐regulated proteins participated in cytoskeletal functions, antiapoptosis, proteasome activity, NF‐κB signaling, cancer cell proliferation, invasion, and angiogenesis. Western immunoblotting were implemented to confirm the deregulated proteins and the downstream signaling proteins. The analytical results of this study help to provide insight into the molecular mechanism of inducing prostate cancer cell apoptosis by pomegranate fruit juice and to develop a novel mechanism‐based chemopreventive strategy for prostate cancer.     

Fibronectin promotes cervical cancer tumorigenesis through activating FAK signaling pathway

Cervical cancer is a cancer arising from the cervix, and it is the fourth most common cause of death in women. Overexpression of fibronectin 1 (FN1) was observed in many tumors and associated with the survival and metastasis of cancer cells. However, the mechanism by which FN1 promotes cervical cancer cell viability, migration, adhesion, and invasion, and inhibits cell apoptosis through focal adhesion kinase (FAK) signaling pathway remains to be investigated. Our results demonstrated that FN1 was upregulated in patients with cervical cancer and higher FN1 expression correlated with a poor prognosis for patients with cervical cancer. FN1 knockdown by small interfering RNA (siRNA) inhibited SiHa cell viability, migration, invasion, and adhesion, and promoted cell apoptosis. FN1 overexpression in CaSki cell promoted cell viability, migration, invasion, and adhesion, and inhibited cell apoptosis. Further, phosphorylation of FAK, a main downstream signaling molecule of FN1, and the protein expression of Bcl-2/Bax, matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), and N-cadherin was upregulated in CaSki cells with FN1 overexpression, but caspase-3 protein expression was downregulated. The FAK phosphorylation inhibitor PF573228 inhibited FN1 overexpression-induced expression of those proteins in CaSki cells with FN1 overexpression. In vivo experiment demonstrated that FN1 knockdown significantly inhibited FN1 expression, phosphorylation of FAK, and tumor growth in xenograft from the nude mice. These results suggest that FN1 regulates the viability, apoptosis, migration, invasion, and adhesion of cervical cancer cells through the FAK signaling pathway and is a potential therapeutic target in the treatment of cervical cancer.     

Suppression of Tafazzin promotes thyroid cancer apoptosis via activating the JNK signaling pathway and enhancing INF2-mediated mitochondrial fission

Tafazzin has been found to be associated with tumor progression. Mitochondrial homeostasis regulates cancer cell viability and metastasis. However, the roles of Tafazzin and mitochondrial homeostasis in thyroid cancer have not been explored. The aim of our study is to investigate the influences of Tafazzin on thyroid cancer apoptosis with a focus on mitochondrial fission. Our results indicated that Tafazzin deletion induced death in thyroid cancer via apoptosis. Biological analysis demonstrated that mitochondrial stress, including mitochondrial bioenergetics disorder, mitochondrial oxidative stress, and mitochondrial apoptosis, was activated by Tafazzin deletion. Furthermore, we found that Tafazzin affected mitochondrial stress by triggering inverted formin 2 (INF2)-related mitochondrial fission. The loss of INF2 sustained mitochondrial function and promoted cancer cell survival. Molecular investigation illustrated that Tafazzin regulated INF2 expression via the JNK signaling pathway; moreover, the blockade of JNK prevented Tafazzin-mediated INF2 expression and improved cancer cell survival. Taken together, our results highlight the key role of Tafazzin as a master regulator of thyroid cancer viability via the modulation of INF2-related mitochondrial fission and the JNK signaling pathway. These findings defined Tafazzin deletion and INF2-related mitochondrial fission as tumor suppressors that act by promoting cancer apoptosis via the JNK signaling pathway, with potential implications for new approaches to thyroid cancer therapy.     

Assessment of the antiproliferative and apoptotic roles of sulfonamide carbonic anhydrase IX inhibitors in HeLa cancer cell line

Carbonic anhydrase IX (CA IX) has recently been validated as an antitumor/antimetastatic drug target. In this study, we examined the underlying molecular mechanisms and the anticancer activity of sulfonamide CA IX inhibitors against cervical cancer cell lines. The effects of several sulfonamides on HeLa, MDA-MB-231, HT-29 cancer cell lines, and normal cell lines (HEK-293, PNT-1A) viability were determined. The compounds showed high cytotoxic and apoptotic activities, mainly against HeLa cells overexpressing CA IX. We were also examined for intracellular reactive oxygen species (ROS) production; intra-/extracellular pH changes, for inhibition of cell proliferation, cellular mitochondrial membrane potential change and for the detection of caspase 3, 8, 9, and CA IX protein levels. Of the investigated sulfonamides, one compound was found to possess high cytotoxic and anti-proliferative effects in HeLa cells. The cytotoxic effect occurred via apoptosis, being accompanied by a return of pHe/pHi towards normal values as for other CA IX inhibitors investigated earlier.     

Anhuienoside C inhibits human ovarian cancer cell growth by inducing apoptosis,suppression of cell migration and invasion,and targeting PI3K/AKT/mTOR signaling pathway

The present study was initiated to examine the anticancer effects of Anhuienoside C (AC) against ovarian cancer and postulates the possible molecular mechanism of its action. 3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay was implemented for determination of the effects of AC on cell viability of the ovarian cancer OVACAR-3 cell line. To study cellular morphology, phase contrast microscopy was performed. Apoptosis was examined via acridine orange/ethidium bromide used staining assays. Flow cytometry was used to check the different phases of the cell cycle. Cell migration and invasion assays were performed via transwell chamber assay. The effects of AC on expression of phosphoinositide 3-kinases (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) protein in ovarian cell were assessed using western blotting assay. The results indicated that the cell proliferation rate lowered in AC-treated OVACAR-3 cells as compared to the untreated controls in a dose-dependent manner. Cell morphology changed substantially by the exposure to AC and remained dose dependent. These morphological changes were indicative of apoptotic cell death. Apoptosis analysis showed dose-dependent increase of apoptosis. The cell migration and invasion of OVACAR-3 cells was reduced to a minimum by AC in a dose-dependent manner. Finally, western blotting assay showed blocking of PI3K/AKT/mTOR signaling pathway with increasing AC doses. Taking all together, AC is a potential ovarian cancer inhibitor. It induces its anti-ovarian cancer effects via induction of apoptosis, delaying cell migration and invasion, and blocking PI3K/AKT/mTOR signaling pathway.

     

Pantoprazole Induces Mitochondrial Apoptosis and Attenuates NF-κB Signaling in Glioma Cells

Gastric H⁺/K⁺-ATPase or vacuolar-ATPases (V-ATPases) are critical for the cancer cells survival and growth in the ischemic microenvironment by extruding protons from the cell. The drugs which inhibit V-ATPases are known as proton pump inhibitors (PPIs). In the present study, we aimed to evaluate the anticancer efficacy of pantoprazole (PPZ) and its consequences on NF-κB signaling in glioma cells. We have used MTT and clonogenic assay to show PPZ effect on glioma cell growth. Propidium iodide and rhodamine 123 staining were performed to demonstrate cell cycle arrest and mitochondrial depolarization. TUNEL staining was used to evidence apoptosis after PPZ treatment. Immunoblotting and immunofluorescence microscopy were performed to depict protein levels and localization, respectively. Luciferase assay was performed to confirm NF-κB suppression by PPZ. Our results revealed PPZ treatment inhibits cell viability or growth and induced cell death in a dose- and time-dependent manner. PPZ exposure arrested G0/G1 cyclic phase and increased TUNEL positivity, caspase-3 and PARP cleavage with altered pro and anti-apoptotic proteins. PPZ also induced ROS levels and depolarized mitochondria (Δψm) with increased cytosolic cytochrome c level. Further, PPZ suppressed TNF-α stimulated NF-κB signaling by repressing p65 nuclear translocation. NF-κB luciferase reporter assays revealed significant inhibition of NF-κB gene upon PPZ treatment. PPZ exposure also reduced the expression of NF-κB-associated genes, such as cyclin-D1, iNOS, and COX-2, which indicate NF-κB inhibition. Altogether, the present study disclosed that PPZ exerts mitochondrial apoptosis and attenuates NF-κB signaling suggesting PPZ can be an effective and safe anticancer drug for glioma.     

Matrine promotes apoptosis in SW480 colorectal cancer cells via elevating MIEF1-related mitochondrial division in a manner dependent on LATS2-Hippo pathway

Matrine, an alkaloid compound isolated from Sophora flavescens Ait, has been shown to exert cancer-killing actions in a variety of tumors; however, its anticancer mechanism in colorectal cancer (CRC) is not clear. The goal of our study was to characterize the anticancer effects and molecular mechanisms of matrine in SW480 CRC cells in vitro. Matrine treatment reduced mitochondrial metabolic function and ATP levels, repressed mitochondrial membrane potential, evoked mitochondrial reactive oxygen species accumulation, and promoted cyt-c-related mitochondrial apoptosis activation. In addition, we found that matrine treatment activated mitochondrial fission through upregulating mitochondrial elongation factor 1 (MIEF1); silencing of MIEF1 prevented matrine-mediated mitochondrial damage and reversed the decrease in SW480 cell viability. Moreover, matrine treatment affected MIEF1 expression via the large tumor suppressor-2 (LATS2)-Hippo axis, and LATS2 deficiency suppressed the anticancer actions exerted by matrine on SW480 cancer cells. In summary, we show for the first time that matrine inhibits SW480 cell survival by activating MIEF1-related mitochondrial division via the LATS2-Hippo pathway. These findings explain the anticancer mechanisms of matrine in CRC and also identify the LATS2-MIEF1 signaling pathway as an effective target for the treatment of CRC.     

Dehydrocostus lactone inhibits cell proliferation and induces apoptosis by PI3K/Akt/Bad and ERS signalling pathway in human laryngeal carcinoma

The anti-cancer effect of dehydrocostus lactone (DHL) derived from Saussurea costus (Falc.) Lipech against laryngeal carcinoma was assessed. The cytotoxic activity of DHL against laryngeal carcinoma is still obscure. Therefore, our study investigated the role of DHL in the growth inhibition of laryngeal carcinoma in vitro and in vivo, and the molecular mechanism of DHL-induced apoptosis in cancer cells of the larynx. The results showed that DHL inhibits the viability, migration and proliferation of Hep-2 and TU212 cells with little toxic effects on human normal larynx epithelial HBE cell line. Flow cytometry analysis (FAC) analysis and staining assay (Hoechst 33258) indicated that DHL stimulated Hep-2 and TU212 cell apoptosis in a dose-dependent manner. Mechanistically, DHL is capable of inhibiting Hep-2 and TU212 cell viability via promoting p53 and P21 function, meanwhile DHL dose-dependently induces Hep-2 and TU212 cells apoptosis via activating mitochondrial apoptosis by inhibiting PI3K/Akt/Bad pathway and stimulating endoplasmic reticulum stress-mediated apoptosis pathway. In vivo, DHL inhibited the growth of the Hep-2 nude mouse xenograft model and observed no significant signs of toxicity in the organs of nude mice. In vivo experiments further confirmed the anti-cancer effect of DHL on laryngeal carcinoma cells in vitro, and DHL-treated nude mice can reduce the volume of tumours. Together, our study indicated that DHL has the potential to inhibit human laryngeal carcinoma via activating mitochondrial apoptosis pathway by inhibiting PI3K/Akt/Bad signalling pathway and stimulating endoplasmic reticulum stress-mediated apoptosis pathway, providing a strategy for the treatment of human laryngeal carcinoma.     

Geraniin suppresses ovarian cancer growth through inhibition of NF‐κB activation and downregulation of Mcl‐1 expression

This study investigated the anticancer effects of geraniin on ovarian cancer cells and the signaling pathways involved. Ovarian cancer cells were treated with different concentrations of geraniin for 48 h and examined for viability, apoptosis, mitochondrial membrane depolarization, and gene expression. Xenograft tumor studies were performed to determine the anticancer activity of geraniin in vivo. Geraniin significantly decreased cancer cell viability in a concentration‐dependent fashion. Geraniin significantly triggered apoptosis, which was accompanied by loss of mitochondrial membrane potential and increased cytochrome c release and caspsase‐3 activity. Mechanistically, geraniin significantly downregulated Mcl‐1 and impaired NF‐κB p65 binding to the mcl‐1 promoter. Overexpression of Mcl‐1 significantly reversed geraniin‐induced apoptosis in OVCAR3 cells. In addition, geraniin retarded ovarian cancer growth and reduced expression of phospho‐p65 and Mcl‐1. Collectively, geraniin elicits growth suppression in ovarian cancer through inhibition of NF‐κB and Mcl‐1 and may provide therapeutic benefits for this malignancy.     

Tanshinone IIA reduces SW837 colorectal cancer cell viability via the promotion of mitochondrial fission by activating JNK-Mff signaling pathways

Background

Mitochondrial homeostasis has been increasingly viewed as a potential target of cancer therapy, and mitochondrial fission is a novel regulator of mitochondrial function and apoptosis. The aim of our study was to determine the detailed role of mitochondrial fission in SW837 colorectal cancer cell viability, mobility and proliferation. In addition, the current study also investigated the therapeutic impact of Tanshinone IIA (Tan IIA), a type of anticancer adjuvant drug, on cancer mitochondrial homeostasis.

Results

The results of our data illustrated that Tan IIA promoted SW837 cell death, impaired cell migration and mediated cancer proliferation arrest in a dose-dependent manner. Functional investigation exhibited that Tan IIA treatment evoked mitochondrial injury, as witnessed by mitochondrial ROS overproduction, mitochondrial potential collapse, antioxidant factor downregulation, mitochondrial pro-apoptotic protein upregulation, and caspase-9-dependent apoptotic pathway activation. Furthermore, we confirmed that Tan IIA mediated mitochondrial damage by activating mitochondrial fission, and the inhibition of mitochondrial fission abrogated the proapoptotic effects of Tan IIA on SW837 cells. To this end, our results demonstrated that Tan IIA modulated mitochondrial fission via the JNK-Mff pathways. The blockade of the JNK-Mff axis inhibited Tan IIA-mediated mitochondrial fission and promoted the survival of SW837 cells.

Conclusions

Altogether, our results identified mitochondrial fission as a new potential target to control cancer viability, mobility and proliferation. Furthermore, our findings demonstrate that Tan IIA is an effective drug to treat colorectal cancer by activating JNK-Mff-mitochondrial fission pathways.

     

OGDHL Is a Modifier of AKT-Dependent Signaling and NF-κB Function

Oxoglutarate dehydrogenase (OGDH) is the first and rate-limiting component of the multi-enzyme OGDH complex (OGDHC) whose malfunction is associated with neuro-degeneration. The essential role of this complex is in the degradation of glucose and glutamate and the OGDHL gene (one component of OGDHC) is down-regulated by promoter hypermethylation in many different cancer types. These properties suggest a potential growth modulating role of OGDHL in cancer; however, the molecular mechanism through which OGDHL exerts its growth modulating function has not been elucidated.Here, we report that restoration of OGDHL expression in cervical cancer cells lacking endogenous OGDHL expression suppressed cell proliferation, invasion and soft agar colony formation in vitro. Knockdown of OGDHL expression in cervical cancer cells expressing endogenous OGDHL had the opposite effect. Forced expression of OGDHL increased the production of reactive oxygen species (ROS) leading to apoptosis through caspase 3 mediated down-regulation of the AKT signaling cascade and decreased NF-κB phosphorylation. Conversely, silencing OGDHL stimulated the signaling pathway via increased AKT phosphorylation. Moreover, the addition of caspase 3 or ROS inhibitors in the presence of OGDHL increased AKT signaling and cervical cancer cell proliferation.Taken together, these data suggest that inactivation of OGDHL can contribute to cervical tumorigenesis via activation of the AKT signaling pathway and thus support it as an important anti-proliferative gene in cervical cancer.     

Molecular mechanism of apoptosis induction by Gaillardin,a sesquiterpene lactone,in breast cancer cell lines

Medicinal plant extracts have been widely used for cancer treatment. Gaillardin is a natural sesquiterpene lactone that has recently been reported to have anticancer properties. The ability to induce apoptosis is an important property of a candidate anticancer drug, which discriminates between anticancer drugs and toxic compounds. The current study was therefore carried out to address the issue if Gaillardin is able to induce apoptosis in the breast cancer cell lines MCF-7 and MDA-MB-468 and to determine the underlying mechanism of its anticancer effects. Apoptosis induction by Gaillardin treatment was confirmed by annexin V–FITC/PI staining, and caspase-3,-6, and-9 activation. Using Western blot analysis, we found that Gaillardin upregulated the pro-apoptotic protein Bax and p53 and downregulated the anti-apoptotic protein Bcl-2. Moreover, the apoptotic effect of Gaillardin was also related to ROS production and loss of mitochondrial membrane potential (ΔΨm). Taken together, these results demonstrate that Gaillardin can inhibit proliferation of breast cancer cells via inducing mitochondrial apoptotic pathway and therefore, might be a promising molecule in cancer chemoprevention or chemotherapy.     

Knockdown of EpCAM Enhances the Chemosensitivity of Breast Cancer Cells to 5-fluorouracil by Downregulating the Antiapoptotic Factor Bcl-2

Resistance to fluoropyrimidine-based chemotherapy is the main reason for the failure of cancer treatment, and drug resistance is associated with an inability of tumor cells to undergo apoptosis in response to treatment. Alterations in the expression of epithelial cell adhesion molecule (EpCAM) affect the sensitivity or resistance of tumor cells to anticancer treatment and the activity of intracellular signaling pathways. However, the role of EpCAM in the induction of apoptosis in breast cancer cells remains unclear. Here, we investigated the effect of EpCAM gene knockdown on chemosensitivity to 5-fluorouracil (5-FU) in MCF-7 cells and explored the underlying mechanisms. Our results showed that knockdown of EpCAM promoted apoptosis, inhibited cell proliferation and caused cell-cycle arrest. EpCAM knockdown enhanced the cytotoxic effect of 5-FU, promoting apoptosis by downregulating the expression of the anti-apoptotic protein Bcl-2 and upregulating the expression of the pro-apoptotic proteins Bax, and caspase3 via the ERK1/2 and JNK MAPK signaling pathways in MCF-7 cells. These results indicate that knockdown of EpCAM may have a tumor suppressor effect and suggest EpCAM as a potential target for the treatment of breast cancer.