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An overview of human pluripotent stem cell applications for the understanding and treatment of blindness
Published in John Ravenscroft, The Routledge Handbook of Visual Impairment, 2019
Louise A. Rooney, Duncan E. Crombie, Grace E. Lidgerwood, Maciej Daniszewski, Alice Pébay
Development of retinal cells can be mimicked in vitro, and many protocols have been published on the differentiation of hPSCs into RPE cells. RPE differentiation can been achieved with harvesting and expanding RPE cells from spontaneously differentiating hPSCs, but the major drawback of this method is the long differentiation period, often over 4–6 months (Buchholz et al., 2009; Buchholz et al., 2013; Vaajasaari et al., 2011; Zahabi et al., 2012). Guided differentiation methods have proven to be great alternatives, as they are more reproducible and faster. Various molecules have been described as efficient for the generation of RPE cells, including basic fibroblast growth factor (bFGF), Noggin, Dickkopf-1 (DKK1), Insulin Growth Factor 1 (IGF1), nicotinamide, casein kinase I inhibitor 7, the ALK4 inhibitor SB-431542 and the Rho-associated kinase inhibitor Y-27632 (Buchholz et al., 2013; Idelson et al., 2009; Kuwahara et al., 2015; Lidgerwood et al., 2016; Osakada et al., 2009; Reichman et al., 2014). An enrichment of retinal cells prior to RPE isolation and expansion can also be used (Cho et al., 2012; Lamba et al., 2006; Lamba et al., 2010; Nakano et al., 2012; Reichman et al., 2014; Sluch et al., 2015; Zhu et al., 2013).
TGFβ1/integrin β3 positive feedback loop contributes to acquired EGFR TKI resistance in EGFR-mutant lung cancer
Published in Journal of Drug Targeting, 2023
Tao Wang, Yali Zhang, Hanyue Cheng, Ling Li, Lu Xu
In our previous study, we found that TGFβ1 could dramatically and consistently induce integrin β3 expression on transcriptional level and activate downstream signalling [8]. As expected, in this study, we used TGFβRI inhibitor SB-431542 to block TGFβ1 signalling and found that integrin β3 expression was reduced on transcriptional level and downstream FAK, Src and Erk signalling was inhibited, further demonstrating that TGFβ1 positively regulate integrin β3 signalling. Furthermore, integrin αv has been reported to locally activate TGFβ1, while other integrins remained to be confirmed [15]. Therefore, to investigate the effects of integrin β3 on TGFβ1 activation and expression in EGFR-mutant lung cancer, we used lentivirus to overexpress and siRNA to knockdown integrin β3 or integrin αvβ3 inhibitor c(RGDfK) to inhibit integrin β3 downstream signalling and found that integrin β3 could positively regulate TGFβ1 production on transcriptional, secretion and activation of downstream SMAD signalling. Moreover, exogenous TGFβ1-induced or osimertinib-induced integrin β3 expression and downstream FAK, Src and Erk signalling activation was abrogated by SB-431542, while osimertinib-induced integrin β3 expression and downstream Smad signalling activation was abrogated by c(RGDfK). Also, the inhibition of SMAD signalling by c(RGDfK) was recovered by exogenous TGFβ1. Put together, our study first showed that TGFβ1 and integrin β3 formed a positive feedback loop by reciprocally inducing the expression of each other on transcriptional level and activating reciprocal downstream signalling.
A novel anticancer chromeno-pyrimidine analogue inhibits epithelial-mesenchymal transition in lung adenocarcinoma cells
Published in Toxicology Mechanisms and Methods, 2021
Venkateswarareddy Nallajennugari, Sankar Pajaniradje, Srividya Subramanian, Suhail Ahmad Bhat, Parthasarathi D, Savitha Bhaskaran, Syed Ali Padusha M, Rukkumani Rajagopalan
Progression and inhibition of cancer and EMT is regulated by a wide variety of proteins, enzymes and transcription factors. Prediction of involvement of some of these proteins which participate in relevant upstream and downstream pathways, was carried out by the use of molecular docking. Metastasis and EMT-related proteins such as TGFβ type 1 receptor, Frizzled-7 CRD and snail1 were docked with CP4b as well as with the standard drugs bound to the crystal structure in the database. TGF-β signaling is implicated in cell proliferation and induction of epithelial mesenchymal transition (EMT) (Xu et al. 2009). TGF-β signaling is considered a suitable therapeutic target especially in advanced cancers. Competitive inhibitors for the ATP-binding site of TGFβ type 1 receptor (TGFβR1) kinase domain have been found to be effective blockers of EMT in pancreatic cancer, and tumor cell migration in mouse mammary epithelial cells (Nagaraj and Datta 2010). Comparative analysis of CP4b and the standard drug (SB-431542) shows high glide g-score and glide energy in the standard drug than CP4b. This indicates that CP4b may not bind to TGFβR1 with the same affinity as that of the standard drug. However, TGFβR1 may be a highly probable target of the drug within the cancer cells since it has the highest g-score out of the three proteins docked with CP4b. Since CP4b may interact with TGFβR1, we hypothesize that the drug might be blocking EMT by binding to the kinase domain of TGFβR1.
CYTL1 inhibits tumor metastasis with decreasing STAT3 phosphorylation
Published in OncoImmunology, 2019
Xiaolin Wang, Ting Li, Yingying Cheng, Pingzhang Wang, Wanqiong Yuan, Qiyao Liu, Fan Yang, Qiang Liu, Dalong Ma, Shigang Ding, Jun Wang, Wenling Han
We have verified that CYTL1 inhibited the migration of multiple types of tumor cells. Both CYTL1 overexpression in tumor cells and treatment with CYTL1 protein revealed that CYTL1 exerted a similar inhibitory effect on migration. Therefore, CYTL1 might exert its function through a specific receptor in tumor cells. In a previous study, we confirmed that CYTL1 exhibited chemotactic activity on monocytes/macrophages through CCR2.9 To determine whether CYTL1 exerts its tumor-suppressing effect through CCR2 in tumor cells, we first detected CCR2 expression in A549 cells. Results in Figure 5a–b showed a low level of CCR2 in A549 cells. Transwell assays of A549 cells treated with CYTL1 only or combined with the CCR2 antagonist RS504393 were performed. The results showed that the CCR2 antagonist did not reverse the inhibitory effect of CYTL1 (Figure 5c), indicating that CYTL1 inhibited the metastasis of tumor cells through other receptors, which remains to be identified. In addition, Jooyeon Kim et al demonstrated that the promotion effect of CYTL1 on cardiac fibrosis was completely abrogated by co-treatment with SB-431542, an antagonist of TGF-β receptor 1.26 These results suggested that TGF-β receptor 1 might be a functional receptor of CYTL1. However, our western blotting results showed that SB-431542 did not reverse the inhibitory effect of CYTL1 on STAT3 (Figure 5d).