scholarly journals PFKFB3 Inhibition Attenuates Oxaliplatin-Induced Autophagy and Enhances Its Cytotoxicity in Colon Cancer Cells

2019 ◽  
Vol 20 (21) ◽  
pp. 5415 ◽  
Author(s):  
Siyuan Yan ◽  
Nan Zhou ◽  
Deru Zhang ◽  
Kaile Zhang ◽  
Wenao Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Viability ◽  
Cancer Cells ◽  
Glycolytic Enzyme ◽  
Cancer Drug ◽  
Autophagic Flux ◽  
Dependent Manner ◽  
Anti Cancer ◽  
Colorectal Cancer Cells ◽  
And Migration

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3), a glycolytic enzyme highly expressed in cancer cells, has been reported to participate in regulating metabolism, angiogenesis, and autophagy. Although anti-cancer drug oxaliplatin (Oxa) effectively inhibits cell proliferation and induces apoptosis, the growing resistance and side-effects make it urgent to improve the therapeutic strategy of Oxa. Although Oxa induces the autophagy process, the role of PFKFB3 in this process remains unknown. In addition, whether PFKFB3 affects the cytotoxicity of Oxa has not been investigated. Here, we show that Oxa-inhibited cell proliferation and migration concomitant with the induction of apoptosis and autophagy in SW480 cells. Both inhibition of autophagy by small molecule inhibitors and siRNA modification decreased the cell viability loss and apoptosis induced by Oxa. Utilizing quantitative PCR and immunoblotting, we observed that Oxa increased PFKFB3 expression in a time- and dose-dependent manner. Meanwhile, suppression of PFKFB3 attenuated both the basal and Oxa-induced autophagy, by monitoring the autophagic flux and phosphorylated-Ulk1, which play essential roles in autophagy initiation. Moreover, PFKFB3 inhibition further inhibited the cell proliferation/migration, and cell viability decreased by Oxa. Collectively, the presented data demonstrated that PFKFB3 inhibition attenuated Oxa-induced autophagy and enhanced its cytotoxicity in colorectal cancer cells.

scholarly journals Furanoic Lipid F-6, A Novel Anti-Cancer Compound that Kills Cancer Cells by Suppressing Proliferation and Inducing Apoptosis

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 960 ◽  
Author(s):  
Jassim M. Al-Hassan ◽  
Yuan Fang Liu ◽  
Meraj A. Khan ◽  
Peiying Yang ◽  
Rui Guan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Neutrophil Extracellular Trap ◽  
Cancer Drug ◽  
Drug Candidate ◽  
Cell Recovery ◽  
Network Analyses ◽  
Anti Cancer

Identifying novel anti-cancer drugs is important for devising better cancer treatment options. In a series of studies designed to identify novel therapeutic compounds, we recently showed that a C-20 fatty acid (12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid, a furanoic acid or F-6) present in the lipid fraction of the secretions of the Arabian Gulf catfish skin (Arius bilineatus Val.; AGCS) robustly induces neutrophil extracellular trap formation. Here, we demonstrate that a lipid mix (Ft-3) extracted from AGCS and F-6, a component of Ft-3, dose dependently kill two cancer cell lines (leukemic K-562 and breast MDA MB-231). Pure F-6 is approximately 3.5 to 16 times more effective than Ft-3 in killing these cancer cells, respectively. Multiplex assays and network analyses show that F-6 promotes the activation of MAPKs such as Erk, JNK, and p38, and specifically suppresses JNK-mediated c-Jun activation necessary for AP-1-mediated cell survival pathways. In both cell lines, F-6 suppresses PI3K-Akt-mTOR pathway specific proteins, indicating that cell proliferation and Akt-mediated protection of mitochondrial stability are compromised by this treatment. Western blot analyses of cleaved caspase 3 (cCasp3) and poly ADP ribose polymerase (PARP) confirmed that F-6 dose-dependently induced apoptosis in both of these cell lines. In 14-day cell recovery experiments, cells treated with increasing doses of F-6 and Ft-3 fail to recover after subsequent drug washout. In summary, this study demonstrates that C-20 furanoic acid F-6, suppresses cancer cell proliferation and promotes apoptotic cell death in leukemic and breast cancer cells, and prevents cell recovery. Therefore, F-6 is a potential anti-cancer drug candidate.

Palladium (II) Complex Enhances ROS-Dependent Apoptotic Effects via Autophagy Inhibition and Disruption of Multiple Signaling Pathways in Colorectal Cancer Cells

2020 ◽  
Vol 20 ◽  
Author(s):  
Seyma Aydinlik ◽  
Merve Erkisa ◽  
Ferda Ari ◽  
Serap Celikler ◽  
Engin Ulukaya
Keyword(s):  
Colorectal Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Annexin V ◽  
Mitochondrial Pathway ◽  
Autophagic Flux ◽  
Colorectal Cancer Cells ◽  
Autophagy Inhibition ◽  
Ht 29

Background: Inhibition of autophagy is reported to be a therapeutically effective strategy in overcoming the resistance that is a deadly outcome in cancer. One of the most common reasons for chemo-resistance to treatment is the patients with tumors exhibiting a KRAS mutation which occurs in approximately 40% of colorectal cancer patients. Objective: Hence, we assessed whether a palladium (Pd)(II) complex is a promising anticancer complex, compared to 5-fluorouracil in KRAS wt HT-29 and KRAS mutant HCT-15 cells. Methods: HCT-15 and HT-29 cells were used for colorectal cancer and chloroquine (CQ) was used as an inhibitor of autophagy. In this context, cells were treated with Pd(II) complex and 5-FU in combination with CQ for 48 h and cell viability was measured by SRB assay. Cell death mode was examined with M30 and M65 ELISA assays, annexin V/propidium iodide. Autophagy was determined by acridine orange (AO) staining. Furthermore, the expression of various autophagy and apoptosis related proteins were evaluated with Western blotting.Luminex assay and reactive oxygen species (ROS) level were examined. Results: Cell viability was decreased in a dose dependent matter and CQ enhances cytotoxic effect in Pd(II) and 5-FU treated cells in colorectal cancer cells. Our data showed that inhibition of autophagic flux significantly increase intrinsic apoptosis through the activation of ROS. We showed that combinatorial treatment with CQ induces apoptosis via the caspase-dependent mitochondrial pathway. Luminex analysis revealed that the combination resulted in a down-regulation of a NF-κB/AKT/CREB signaling pathways in both cell line, however, decreased Erk1/2 protein expression was only observed after treated with CQ combination in HCT-15 cells. Conclusion: We suggest that inhibition of autophagy along with Pd(II) and 5-FU treatment has a synergistic effect in KRAS-mutant colorectal cancer cells. Autophagy inhibition by CQ promotes apoptosis via blockade of the NF-κB/AKT/CREB and activation of ROS.

scholarly journals Controlled pharmacokinetic anti-cancer drug concentration profiles lead to growth inhibition of colorectal cancer cells in a microfluidic device

Lab on a Chip ◽  
2020 ◽  
Vol 20 (17) ◽  
pp. 3167-3178
Author(s):  
Job Komen ◽  
Eiko Y. Westerbeek ◽  
Ruben W. Kolkman ◽  
Julia Roesthuis ◽  
Caroline Lievens ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Microfluidic Device ◽  
Concentration Profile ◽  
Cancer Drug ◽  
Concentration Profiles ◽  
Anti Cancer ◽  
Colorectal Cancer Cells ◽  
On Chip

We present a microfluidic device to expose cancer cells to a dynamic, in vivo-like concentration profile of a drug, and quantify efficacy on-chip.

scholarly journals PD-1 Blockade Delays Tumor Growth by Inhibiting an Intrinsic SHP2/Ras/MAPK Signalling in Thyroid Cancer Cells

2020 ◽  
Author(s):  
Federica Liotti ◽  
Narender Kumar ◽  
Nella Prevete ◽  
Maria Marotta ◽  
Daniela Sorriento ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Mapk Signalling ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC).Methods: PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR; western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice.Results: Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation.Conclusions: PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.

scholarly journals A cell-autonomous PD-1/PD-L1 circuit promotes tumorigenicity of thyroid cancer cells by activating a SHP2/Ras/MAPK signalling cascade

2020 ◽  
Author(s):  
Federica Liotti ◽  
Narender Kumar ◽  
Nella Prevete ◽  
Maria Marotta ◽  
Daniela Sorriento ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Mapk Pathway ◽  
Immune Checkpoints ◽  
Ras Activation ◽  
Anti Cancer ◽  
Mapk Signalling ◽  
A Cell ◽  
And Migration

AbstractThe programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2 are immune checkpoints. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their anti-cancer activity. Recently, PD-1 expression has been found in cancer cells. We analysed expression and functions of PD-1 in thyroid cancer (TC). Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 overexpression/stimulation promoted TC cell proliferation and migration in culture. PD-1 recruited the SHP2 phosphatase, potentiated its phosphatase activity thus enhancing Ras activation by dephosphorylation of inhibitory tyrosine 32 and triggering the MAPK cascade. PD-1 inhibition decreased, while PD-1 overexpression facilitated, TC cell xenograft growth by affecting cell proliferation. PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the Ras/MAPK pathway.

scholarly journals Ligustrazine inhibits the proliferation and migration of ovarian cancer cells via regulating miR-211

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Hairong Zhang ◽  
Shichao Ding ◽  
Lei Xia
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Anti Cancer ◽  
And Migration ◽  
The Impact ◽  
Proliferation And Migration

Abstract Ovarian cancer (OC) is a commonly diagnosed female cancer. Ligustrazine (LSZ), a natural compound, has been reported to exert anti-cancer activity, although the mechanisms underlying the anti-cancer effects are not clear. The present study investigated the impact of LSZ on cell proliferation and migration by regulating microRNA-211 (miR-211) expression using the human ovarian cancer SK-OV-3 and OVCAR-3 cell lines. OC cells were treated with 0, 0.5, 1, and 2 mM LSZ, and quantitative real-time PCR was utilized to measure miR-211 levels in SK-OV-3 and OVCAR-3 cells with different treatment. Moreover, to further confirm the roles of miR-211 in LSZ induced anti-tumor effects, miR-211 expression was inhibited by transfection of miR-211 inhibitors in SK-OV-3 cells. Cell proliferation of transfected cells was evaluated using the CCK-8 and colony formation assay. The scratch assay was employed to assess cell migration and transwell assay was performed for evaluating the cell invasion. Protein levels of epithelial–mesenchymal transition (EMT) markers were determined by Western blotting. We found that LSZ inhibited the viability, proliferation, migration and invasion ability of SK-OV-3 and OVCAR-3 cells in a dose-dependent manner; moreover, LSZ could significantly increase the expression of miR-211 in both SK-OV-3 and OVCAR-3, and knockdown of miR-211 in SK-OV-3 cells partially abrogated the anti-tumor behavior of LSZ by promoting the viability, proliferation, migration, invasion and EMT of SK-OV-3 cells. Thus, we found that LSZ can inhibit the proliferation and migration of OC cells via regulating miR-211. Our study suggests that LSZ might be a potential and effective treatment for OC.

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