Deep-Learning-Based Deconvolution of Mechanical Stimuli with Ti3C2Tx MXene Electromagnetic Shield Architecture via Dual-Mode Wireless Signal Variation Mechanism.

Passive component-based soft resonators have been spotlighted in the field of wearable and implantable devices due to their remote operation capability and tunable properties. As the output signal of the resonator-based wireless communication device is given in the form of a vector (i.e., a spectrum of reflection coefficient), multiple information can, in principle, be stored and interpreted. Herein, we introduce a device that can deconvolute mechanical stimuli from a single wireless signal using dual-mode operation, specifically enabled by the use of Ti3C2Tx MXene. MXene's strong electromagnetic shielding effect enables the resonator to simultaneously measure pressure and strain without overlapping its output signal, unlike other conductive counterparts that are deficient in shielding ability. Furthermore, convolutional neural-network-based deep learning was implemented to predict the pressure and strain values from unforeseen output wireless signals. Our MXene-integrated wireless device can also be utilized as an on-skin mechanical stimuli sensor for rehabilitation monitoring after orthopedic surgery. The dual-mode signal variation mechanism enabled by integration of MXene allows wireless communication systems to efficiently handle various information simultaneously, through which multistimuli sensing capability can be imparted into passive component-based wearable and implantable electrical devices.

Protein kinase CK2 activation is required for transforming growth factor ß-induced epithelial-mesenchymal transition.

Transforming growth factor ß (TGFß) is overexpressed in advanced cancers and promotes tumorigenesis by inducing epithelial-mesenchymal transition (EMT), which enhances invasiveness and metastasis. Although we previously reported that EMT could be induced by increasing CK2 activity alone, it is not known whether CK2 also plays an essential role in TGFß-induced EMT. Therefore, in the present study, we investigated whether TGFß signaling could activate CK2 and, if so, whether such activation is required for TGFß-induced EMT. We found that CK2 is activated by TGFß treatment, and that activity peaks at 48 h after treatment. CK2 activation is dependent on TGFß receptor (TGFBR) I kinase activity, but independent of SMAD4. Inhibition of CK2 activation through the use of either a CK2 inhibitor or shRNA against CSNK2A1 inhibited TGFß-induced EMT. TGFß signaling decreased CK2ß but did not affect CK2α protein levels, resulting in a quantitative imbalance between the catalytic α and regulatory ß subunits, thereby increasing CK2 activity. The decrease in CK2ß expression was dependent on TGFBRI kinase activity and the ubiquitin-proteasome pathway. The E3 ubiquitin ligases responsible for TGFß-induced CK2ß degradation were found to be CHIP and WWP1. Okadaic acid (OA) pretreatment protected CK2ß from TGFß-induced degradation, suggesting that dephosphorylation of CK2ß by an OA-sensitive phosphatase might be required for CK2 activation in TGFß-induced EMT. Collectively, our results suggest CK2 as a therapeutic target for the prevention of EMT and metastasis of cancers.

Phosphorylation-dependent stabilization of MZF1 upregulates N-cadherin expression during protein kinase CK2-mediated epithelial-mesenchymal transition.

Epithelial-mesenchymal transition (EMT) is a critical process in invasion and metastasis of cancer cells. E-cadherin to N-cadherin switching is considered a molecular hallmark of EMT. Recently, we reported that increased CK2 activity fully induces E-cadherin to N-cadherin switching, but the molecular mechanisms of N-cadherin upregulation are unknown. In this study, we examined how N-cadherin is upregulated by CK2. N-cadherin promoter analysis and ChIP analysis identified and confirmed myeloid zinc finger 1 (MZF1) as an N-cadherin transcription factor. Molecular analysis showed that MZF1 directly interacts with CK2 and is phosphorylated at serine 27. Phosphorylation stabilizes MZF1 and induces transcription of N-cadherin. MZF1 knockdown (MKD) in N-cadherin-expressing cancer cells downregulates N-cadherin expression and reverts the morphology from spindle and fibroblast-like to a rounded, epithelial shape. In addition, we showed that that MKD reduced the motility and invasiveness of N-cadherin-expressing cancer cells. Collectively, these data indicate that N-cadherin upregulation in CK2-mediated E-cadherin to N-cadherin switching is dependent on phosphorylation-mediated MZF1 stabilization. CK2 could be a good therapeutic target for the prevention of metastasis.

Ethyl 2-(benzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate analogues as a new scaffold for protein kinase casein kinase 2 inhibitor.

Protein kinase casein kinase 2 (PKCK2) is a constitutively active, growth factor-independent serine/threonine kinase, and changes in PKCK2 expression or its activity are reported in many cancer cells. To develop a novel PKCK2 inhibitor(s), we first performed cell-based phenotypic screening using 4000 chemicals purchased from ChemDiv chemical libraries (2000: randomly selected; 2000: kinase-biased) and performed in vitro kinase assay-based screening using hits found from the first screening. We identified compound 24 (C24)[(Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a] pyrimidine-6-carboxylate] as a novel inhibitor of PKCK2 that is more potent and selective than 4,5,6,7-tetrabromobenzotriazole (TBB). In particular, compound 24 [half maximal inhibitory concentration (IC50)=0.56µM] inhibited PKCK2 2.2-fold more efficiently than did TBB (IC50=1.24µM), which is quite specific toward PKCK2 with respect to ATP binding, in a panel of 31 human protein kinases. The Ki values of compound 24 and TBB for PKCK2 were 0.78µM and 2.70µM, respectively. Treatment of cells with compound 24 inhibited endogenous PKCK2 activity and showed anti-proliferative and pro-apoptotic effects against stomach and hepatocellular cancer cell lines more efficiently than did TBB. As expected, compound 24 also enabled tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-resistant cancer cells to be sensitive toward TRAIL. In comparing the molecular docking of compound 24 bound to PKCK2α versus previously reported complexes of PKCK2 with other inhibitors, our findings suggest a new scaffold for specific PKCK2α inhibitors. Thus, compound 24 appears to be a selective, cell-permeable, potent, and novel PKCK2 inhibitor worthy of further characterization.

Protein kinase casein kinase 2-mediated upregulation of N-cadherin confers anoikis resistance on esophageal carcinoma cells.

Previously, we reported that high PKCK2 activity could protect cancer cells from death receptor-mediated apoptosis through phosphorylation of procaspase-2. Because anoikis is another form of apoptosis, we asked whether PKCK2 could similarly confer resistance to anoikis on cancer cells. Human esophageal squamous cancer cell lines with high PKCK2 activity (HCE4 and HCE7) were anoikis-resistant, whereas cell lines with low PKCK2 activity (TE2 and TE3) were anoikis-sensitive. Because the cells showed different sensitivity to anoikis, we compared the expression of cell adhesion molecules between anoikis-sensitive TE2 and anoikis-resistant HCE4 cells using cDNA microarray. We found that E-cadherin is expressed only in TE2 cells; whereas N-cadherin is expressed instead of E-cadherin in HCE4 cells. To examine whether PKCK2 activity could determine the type of cadherin expressed, we first increased intracellular PKCK2 activity in TE2 cells by overexpressing the PKCK2α catalytic subunit using lentivirus and found that high PKCK2 activity could switch cadherin expression from type E to N and confer anoikis resistance. Conversely, a decrease in PKCK2 activity in HCE4 cells by knockdown of PKCK2α catalytic subunit using shRNA induced N- to E-cadherin switching and the anoikis-resistant cells became sensitive. In addition, N-cadherin expression correlated with PKB/Akt activation and increased invasiveness. We conclude that high intracellular PKCK2 activity confers anoikis resistance on esophageal cancer cells by inducing E- to N-cadherin switching.