Cinnamaldehyde Derivative (CB-PIC) Sensitizes Chemo-Resistant Cancer Cells to Drug-Induced Apoptosis via Suppression of MDR1 and its Upstream STAT3 and AKT Signalling

Background/Aims: ATG4B is a cysteine protease required for autophagy, which is a cellular catabolic pathway involved in energy balance. ATG4B expression is elevated during tumor growth in certain types of cancer, suggesting that ATG4B is an attractive target for cancer therapy. However, little is known about the mechanisms through which ATG4B deprivation suppresses the growth of cancer cells. Methods: Cancer cells were transfected with either siRNA against ATG4B or an expression vector encoding wild-type ATG4B^WT or encoding catalytic mutant ATG4B^C74A to determine cell cycle progression by propidium iodide staining or by BrdU incorporation assay using flow cytometry. The GFP-MAP1LC3-II puncta and protein levels in the cells were determined by immunofluorescence and immunoblotting, respectively. Results: Knockdown of ATG4B blocked cell proliferation, particularly at the G₁-S phase transition, in various cancer cells. Moreover, knockdown of ATG4B or overexpression of the ATG4B^C74A catalytic mutant reduced both autophagic flux and ATP levels and increased AMP-activated protein kinase (AMPK) phosphorylation in the cancer cells. Nevertheless, knockdown of ATG4B had only a minor effect on AMPK activation and G₁ phase arrest in liver kinase B1 (LKB1)-deficient or AMPK-inhibited cancer cells. Conclusion: These results imply that targeting ATG4B might inhibit autophagy and trigger the LKB1-AMPK energy-sensing pathway, resulting in tumor growth suppression.

Section: Discussionmentioning

confidence: 99%

Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells

Liu

Hsu

Tsai

et al. 2017

“…Arsenic has been shown to be a strong inducer of apoptosis in various models through excessive production of ROS, decreased mitochondrial membrane potential, activation of caspase, increased fragmentation of DNA and impairment of T-cell activity via up-regulation of immune and stress response genes associated with increased production of ROS, which might be involved in the apoptosis and necrosis that it induces in immune cells [10, 33-35]. Earlier reports demonstrated a strong link between immunotoxicity and formation of reactive oxygen species (ROS), which is related to arsenic exposure [36].…”

Section: Discussionmentioning

confidence: 99%

(-)-Epigallocatechin-3-Gallate Inhibits Arsenic-Induced Inflammation and Apoptosis through Suppression of Oxidative Stress in Mice

Yu¹,

Pei

Huang³

et al. 2017

Background/Aims: Exposure to arsenic in individuals has been found to be associated with various health-related problems including skin lesions, cancer, and cardiovascular and immunological disorders. (-)-Epigallocatechin-3-gallate (EGCG), the main and active polyphenolic catechin present in green tea, has shown potent antioxidant, anti-apoptotic and anti-inflammatory activity in vivo and in vitro. Thus, the present study was conducted to investigate the protective effects of EGCG against arsenic-induced inflammation and immunotoxicity in mice. Methods: Serum IL-1β, IL-6 and TNF-α were determined by ELISA, tissue catalase (CAT), malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), nitric oxide and caspase 3 by commercial kits, mitochondrial membrane potential with Rh 123, mitochondrial ROS with 2’,7’-dichlorofluorescin diacetate (DCFH-DA), apoptotic and necrotic cells and T-cell phenotyping with Flow cytometry analysis. Results: The results showed that arsenic treatment significantly increased oxidative stress levels (as indicated by catalase, malonyldialdehyde, superoxide dismutase, glutathione and reactive oxygen species), increased levels of inflammatory cytokines and promoted apoptosis. Arsenic exposure increased the relative frequency of the CD8+(Tc) cell subpopulation (from 2.8 to 18.9%) and decreased the frequency of CD4+(Th) cells (from 5.2 to 2.7%). Arsenic exposure also significantly decreased the frequency of T(CD3) (from 32.5% to 19.2%) and B(CD19) cells (from 55.1 to 32.5%). All of these effects induced by NaAsO₂ were attenuated by EGCG. Conclusions: The present in vitro findings indicate that EGCG attenuates not only NaAsO₂-induced immunosuppression but also inflammation and apoptosis.

“…It is expected that chemicals, such as CB-PIC [29] and SI113 [30], which act on STAT3 [29], AKT [29], and p53 [30], may further influence the activation of NF-κB and its downstream genes, and compensate for the decreased paclitaxel sensitivity by Rsf-1 in NSCLCs. The cross talk between YAP and NF-κB [31] suggests that verteporfin should have the potential to reverse paclitaxel enhanced resistance in NSCLCS [24].…”

Section: Discussionmentioning

confidence: 99%

Rsf-1 Influences the Sensitivity of Non-Small Cell Lung Cancer to Paclitaxel by Regulating NF-κB Pathway and Its Downstream Proteins

Chen

Sun

Guan

et al. 2017

Background/Aims: The therapeutic efficacy of paclitaxel is hampered by chemotherapeutic resistance in non-small cell lung cancer (NSCLC). Rsf-1 enhanced paclitaxel resistance via nuclear factor-κB (NF-κB) in ovarian cancer cells and nasopharyngeal carcinoma. This study assessed the function of Rsf-1 in the modulation of the sensitivity of NSCLC to paclitaxel via the NF-κB pathway. Methods: The mRNA and protein levels of the related genes were quantified by RT-PCR and Western blotting. Rsf-1 silencing was achieved with CRISPR/Cas9 gene editing. Cell cycle, migration and proliferation were tested with flow cytometry, transwell test and CCK8 test. Cell apoptosis was analyzed with flow cytometry and quantification of C-capase3. The parameters of the tumors were measured in H460 cell xenograft mice. Results: Rsf-1 was highly expressed in H460 and H1299 cells. Rsf-1 knockout caused cell arrest at the G1 phase, increased cell apoptosis, and decreased migration and cell proliferation. Rsf-1 knockout increased the inhibition of cell proliferation, the reduction in cell migration and the augment in cell apoptosis in paclitaxel treated H460 and H1299 cells. Rsf-1 knockout further enhanced the paclitaxel-mediated decrease in the volume and weight of the tumors in H460 cell xenograft mice. Helenalin and Rsf-1 knockout decreased the protein levels of p-P65, BcL2, CFLAR, and XIAP; hSNF2H knockout decreased the protein level of NF-κB p-P65 without altering Rsf-1 and p65 protein levels, while Rsf-1 and hSNF2H double knockout decreased the level of NF-κB p-P65, in H1299 and H460 cells. Conclusion: These results demonstrate that Rsf-1 influences the sensitivity of NSCLC to paclitaxel via regulation of the NF-κB pathway and its downstream genes.