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 nonsmall 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 SCF FBW7 , 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.

Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen dysregulates expression of MCL-1 by targeting FBW7

“…Using K48R (Lysine 48 to Arginine) ubiquitin mutant, MCL-1 polyubiquitination was marginally increased when FBW7 was simultaneously overexpressed ( Fig 3B lower panel, compared lane 3 with lane 4) and there was no effect by either LANA or LANA-P1 expression ( Fig 3B lower panel, compared lane 4 with lanes 5 & 6). This result indicates that MCL-1 was mainly modified by K48-linked ubiquitin chain as shown by previous report [ 31 ], and LANA suppresses K48-linked ubiquitination of MCL-1, ultimately leading to the stabilization of MCL-1 ( Fig 3B ).…”

Transcriptome profiling reveals Silibinin dose-dependent response network in non-small lung cancer cells

“…We draw the negative result of BIRC5 knockdown in H838 cells back to constitutively low level of BIRC5 in H838 in comparison to H1975, A549 cell lines. The relative changes in SIL response between control and knocked down NSCNC cells observed in this work are in the order of magnitude comparable with previous observations for other small weight compounds and NSCLC cell lines ( Gao et al., 2020 ).…”

An Electrophilic Deguelin Analogue Inhibits STAT3 Signaling in H-Ras-Transformed Human Mammary Epithelial Cells: The Cysteine 259 Residue as a Potential Target

“…For instance, curcumin, betulinic acid, capsaicin, caffeic acid, celastrol, cucurbitacins, guggulsterone, diosgenin, and honokiol are known to be natural STAT3 inhibitors [ 47 ]. Deguelin, a rotenoid isolated from several tropical plants of the Leguminosae family, was reported to inhibit STAT3 signaling, which accounts for its antiproliferative activity towards some transformed and cancerous cells [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. In an attempt to enhance its efficacy while minimizing the side effects, a series of analogues of deguelin have been synthesized and tested for their capabilities to suppress STAT3 activation [ 40 ].…”

“…Deguelin is a natural rotenoid that is isolated from several medicinal plants, including Derris trifoliata Lour (Leguminosae), Mundulea sericea (Leguminosae), and Tephrosia vogelii Hook.f (Leguminosae) [ 3 ]. Deguelin inhibits the proliferation and growth of diverse malignant cells, including head and neck [ 4 , 5 ], lung [ 6 ], esophageal [ 7 ], gastric [ 8 ]. colon [ 9 ], pancreatic [ 10 , 11 ], prostate [ 12 ], and breast [ 13 , 14 ] cancer cells by targeting multiple signaling molecules.…”