Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/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 GSK3β 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 GSK3β is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3β 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.

• Authors: Feng Gao, Xinfang Yu, Ming Li, Li Zhou, Wenbin Liu, Wei Li, Haidan Liu
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 2 Pg. 143 (02 21 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32081857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• F-Box-WD Repeat-Containing Protein 7
• FBXW7 protein, human
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Protein Kinase Inhibitors
• Rotenone
• EGFR protein, human
• ErbB Receptors
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• deguelin

Topics

• A549 Cells
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, genetics, pathology)
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• F-Box-WD Repeat-Containing Protein 7 (metabolism)
• Female
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• Lung Neoplasms (drug therapy, enzymology, genetics, pathology)
• Mice, Nude
• Mutation
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology)
• Protein Stability
• Rotenone (analogs & derivatives, pharmacology)
• Signal Transduction
• Tumor Burden (drug effects)
• Ubiquitination
• Xenograft Model Antitumor Assays