Inhibition of cytoplasmic GSK-3β increases cisplatin resistance through activation of Wnt/β-catenin signaling in A549/DDP cells

Gao, Yuan; Liu, Zan; Zhang, Xiuwei; He, Jiani; Pan, Yongqi; Hao, Fengxia; Xie, Lingling; Li, Qingchang; Qiu, Xueshan; Wang, Enhua

doi:10.1016/j.canlet.2013.05.005

Cited by 65 publications

(57 citation statements)

References 38 publications

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“…Several lines of evidence have suggested that the Wnt/PKC signaling pathway was aberrantly activated in some cancer types, in which Wnt5a might activate this signaling and was responsible for metastasis and chemoresistance in cancers in part through activation of Wnt/ β -cateinin signaling [34–37]. Above in vitro studies have clearly showed that the PKC inhibitor GF109203X could sufficiently inhibit the Wnt5a-induced cell migration, invasion, and clonogenicity in both A549 and A549/DDP lung cancer cells, implying that Wnt5a could promote lung cancer cell mobility by activation of Wnt/PKC noncanonical pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Apart from the oncogenic role of Wnt signaling in cancer metastasis and invasion, dysregulations of Wnt signaling pathways, particularly the canonical Wnt pathway, have been demonstrated to contribute to therapeutic resistances in many cancer types [31, 37, 44, 69–72]. In this regard, Wnt5a was also found to modulate cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells [70] and regulates ABCB1 expression in multidrug-resistant breast cancer cells through activation of the noncanonical PKA/beta-catenin pathway [48].…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, Wnt5a was also found to modulate cell cycle progression and contributes to the chemoresistance in pancreatic cancer cells [70] and regulates ABCB1 expression in multidrug-resistant breast cancer cells through activation of the noncanonical PKA/beta-catenin pathway [48]. In the NSCLC cells, activation of Wnt pathway was previously demonstrated to be associated with resistance to platinum-based chemotherapy [37, 50, 73]. Cisplatin-resistant NSCLC cells had increased expression of Wnt pathway genes.…”

Section: Discussionmentioning

confidence: 99%

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Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Yang

Zhang

et al. 2016

Stem Cells International

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The development of chemoresistance to cisplatin regimens causes a poor prognosis in patients with advanced NSCLC. The role of noncanonical Wnt signaling in the regulation of properties of lung cancer stem cells and chemoresistance was interrogated, by accessing capacities of cell proliferation, migration, invasion, and clonogenicity as well as the apoptosis in A549 cell lines and cisplatin-resistant A549 cells treated with Wnt5a conditional medium or protein kinase C (PKC) inhibitor GF109203X. Results showed that the noncanonical Wnt signaling ligand, Wnt5a, could promote the proliferation, migration, invasion, and colony formation in A549 lung adenocarcinoma cells and cisplatin-resistant A549/DDP cells and increase the fraction of ALDH-positive cell in A549/DDP cells. An exposure of cells to Wnt5a led to a significant reduction of A549/DDP cell apoptosis but not A549 cells. An addition of GF109203X could both strikingly increase the baseline apoptosis and resensitize the Wnt5a-inhibited cell apoptosis. Interestingly, an inhibition of Wnt/PKC signaling pathway could reduce properties of lung cancer stem cells, promote cell apoptosis, and resensitize cisplatin-resistant cells to cisplatin via a caspase/AIF-dependent pathway. These data thus suggested that the Wnt5a could promote lung cancer cell mobility and cisplatin-resistance through a Wnt/PKC signaling pathway and a blockage of this signaling may be an alternative therapeutic strategy for NSCLC patients with resistance to chemotherapies.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Yang

Zhang

et al. 2016

Stem Cells International

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“…have active Wnt signaling, and in the A549 cell-line activation of the Wnt pathway has been associated to cisplatin resistance (Gao et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The Novel Anticancer Drug Hydroxytriolein Inhibits Lung Cancer Cell Proliferation via a Protein Kinase Cα– and Extracellular Signal-Regulated Kinase 1/2–Dependent Mechanism

Guardiola-Serrano

Beteta-Göbel

Rodríguez-Lorca

et al. 2015

J Pharmacol Exp Ther

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Membrane lipid therapy is a novel approach to rationally design or discover therapeutic molecules that target membrane lipids. This strategy has been used to design synthetic fatty acid analogs that are currently under study in clinical trials for the treatment of cancer. In this context, and with the aim of controlling tumor cell growth, we have designed and synthesized a hydroxylated analog of triolein, hydroxytriolein (HTO). Both triolein and HTO regulate the biophysical properties of model membranes, and they inhibit the growth of non-small-cell lung cancer (NSCLC) cell lines in vitro. The molecular mechanism underlying the antiproliferative effect of HTO involves regulation of the lipid membrane structure, protein kinase C-a and extracellular signal-regulated kinase activation, the production of reactive oxygen species, and autophagy. In vivo studies on a mouse model of NSCLC showed that HTO, but not triolein, impairs tumor growth, which could be associated with the relative resistance of HTO to enzymatic degradation. The data presented explain in part why olive oil (whose main component is the triacylglycerol triolein) is preventive but not therapeutic, and they demonstrate a potent effect of HTO against cancer. HTO shows a good safety profile, it can be administered orally, and it does not induce nontumor cell (fibroblast) death in vitro or side effects in mice, reflecting its specificity for cancer cells. For these reasons, HTO is a good candidate as a drug to combat cancer that acts by regulating lipid structure and function in the cancer cell membrane.

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“…After GSK-3β is activated, it can form a degradation complex with β-catenin to promote β-catenin degradation. P-GSK-3β (ser9) is the inactive form of GSK-3β, while P-GSK-3β (tyr216) is the active form GSK-3β [19]. To study the effect of Dex on the canonical WNT pathway, TSCs were treated with 1 µM Dex for 3, 5, or 7 days.…”

Section: Chen Et Al: Dickkopf1 Promotes Rtscs To Differentiate Into mentioning

confidence: 99%

Dickkopf1 Up-Regulation Induced by a High Concentration of Dexamethasone Promotes Rat Tendon Stem Cells to Differentiate Into Adipocytes

Chen

Tang

Liu

et al. 2015

Cell Physiol Biochem

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Background/Aims: Dexamethasone (Dex)-induced spontaneous tendon rupture and decreased self-repair capability is very common in clinical practice. The metaplasia of adipose tissue in the ruptured tendon indicates that Dex may induce tendon stem cells (TSCs) to differentiate into adipocytes, but the mechanism remains unclear. In the present study, we used in vitro methods to investigate the effects of Dex on rat TSC differentiation and the molecular mechanisms underlying this process. Methods: First, we used qPCR and Western blotting to detect the expression of the adipogenic differentiation markers aP2 and C/EBPα after treating the TSCs with Dex. Oil red staining was used to confirm that high concentration Dex promoted adipogenic differentiation of rat TSCs. Next, we used qPCR and Western blotting to detect the effect of a high concentration of dexamethasone on molecules related to the canonical WNT/β-catenin pathway in TSCs. Results: Treating rat TSCs with Dex promoted the synthesis of the inhibitory molecule dickkopf1 (DKK1) at the mRNA and protein levels. Western blotting results further showed that Dex downregulated the cellular signaling molecule phosphorylated glycogen synthase kinase-3β (P-GSK-3 β (ser9)), upregulated P-GSK-3β (tyr216), and downregulated the pivotal signaling molecule β-catenin. Furthermore, DKK1 knockdown attenuated Dex-induced inhibition of the canonical WNT/β-catenin pathway and of the adipogenic differentiation of TSCs. Lithium chloride (LiCl, a GSK-3β inhibitor) reduced Dex-induced inhibition of the classical WNT/β-catenin pathway in TSCs and of the differentiation of TSCs to adipocytes. Conclusion: In conclusion, by upregulating DKK1 expression, reducing the level of P-GSK-3β (ser9), and increasing the level of P-GSK-3β (tyr216), Dex causes the degradation of β-catenin, the central molecule of the classical WNT pathway, thereby inducing rat TSCs to differentiate into adipocytes.

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Inhibition of cytoplasmic GSK-3β increases cisplatin resistance through activation of Wnt/β-catenin signaling in A549/DDP cells

Cited by 65 publications

References 38 publications

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

Wnt5a Increases Properties of Lung Cancer Stem Cells and Resistance to Cisplatin through Activation of Wnt5a/PKC Signaling Pathway

The Novel Anticancer Drug Hydroxytriolein Inhibits Lung Cancer Cell Proliferation via a Protein Kinase Cα– and Extracellular Signal-Regulated Kinase 1/2–Dependent Mechanism

Dickkopf1 Up-Regulation Induced by a High Concentration of Dexamethasone Promotes Rat Tendon Stem Cells to Differentiate Into Adipocytes

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