Dataset Information

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3?/FBW7-mediated Mcl-1 destabilization.

ABSTRACT: Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human non-small cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. The in silico docking study indicated that deguelin was docked into the ATP-binding pocket of EGFRs. By suppression of EGFR signaling, deguelin inhibited anchorage-dependent, and independent growth of NSCLC cell lines, and significantly delayed tumorigenesis in vivo. Further study showed that deguelin inhibited EGFR and downstream kinase Akt, which resulted in the activation of GSK3? and eventually enhanced Mcl-1 phosphorylation at S159. Moreover, deguelin promoted the interaction between Mcl-1 and E3 ligase SCFFBW7, which enhanced FBW7-mediated Mcl-1 ubiquitination and degradation. Additionally, phosphorylation of Mcl-1 by GSK3? is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3? compromised deguelin-induced Mcl-1 ubiquitination and reduction. Taken together, our data indicate that enhancement of ubiquitination-dependent Mcl-1 turnover might be a promising approach for cancer treatment.

SUBMITTER: Gao F

PROVIDER: S-EPMC7035355 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization.

Gao Feng F Yu Xinfang X Li Ming M Zhou Li L Liu Wenbin W Li Wei W Liu Haidan H

Cell death & disease 20200221 2

Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human non-small cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. The in silico docking s ...[more]

PMID: 32081857

Similar Datasets

Project description:Deguelin is known to suppress the growth of cancer cells; however, its anti-metastatic effects have not been studied so far in any cancer model. In the present study, we aimed to evaluate the anti-metastatic potential of deguelin in vivo and in tumor growth factor-β1 (TGFβ1)-stimulated cells. Our results demonstrate that tumor growth, peritoneal dissemination and liver/lung metastasis of orthotopically implanted PanC-1-luc cells were significantly reduced in deguelin-treated mice along with the induction of apoptosis. Furthermore, deguelin-treated tumors showed increased epithelial signature such as increased expression of E-Cadherin and cytokeratin-18 and decreased expression of Snail. Similar observations were made when PanC-1, COLO-357 and L3.6pl cells were treated in vitro with deguelin. Moreover, E-cadherin was transcriptionally upregulated and accumulated in the membrane fraction of deguelin-treated cells, as indicated by increased interaction of E-Cadherin with β-catenin. TGFβ1-induced downregulation of E-Cadherin and upregulation of Snail were abrogated by deguelin treatment. In addition, deguelin inhibited TGFβ1-induced Smad3 phosphorylation and Smad4 nuclear translocation in PanC-1 cells. Furthermore, when TGFβ1-induced nuclear factor kappa B (NFκB) activation was inhibited, TGFβ1-induced Snail upregulation or E-Cadherin downregulation was blocked. Deguelin also significantly downregulated the constitutive phosphorylation and DNA binding of NFκB in a dose-dependent manner. Interestingly, overexpression of either NFκB or Snail completely abrogated deguelin-mediated epithelial-to-mesenchymal transition (EMT) inhibition, whereas overexpression of NFκB but not Snail rescued cells from deguelin-induced apoptosis. Hence, deguelin targets NFκB to induce reversal of EMT and apoptosis but downstream effectors might be different for both processes. Taken together, our results suggest that deguelin suppresses both pancreatic tumor growth and metastasis by inducing apoptosis and inhibiting EMT.

Dataset Information

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3?/FBW7-mediated Mcl-1 destabilization.

Publications

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets