Inhibition of Wnt3a/FOXM1/β-Catenin Axis and Activation of GSK3β and Caspases are Critically Involved in Apoptotic Effect of Moracin D in Breast Cancers

Abstract

Although Moracin D derived from Morus alba was known to have anti-inflammatory and antioxidant activities, the underlying antitumor mechanism of Moracin D has not been unveiled thus far. Thus, in the recent study, the apoptotic mechanism of Moracin D was elucidated in breast cancer cells. Herein, Moracin D exerted significant cytotoxicity in MDA-MB-231 and MCF-7 cells. Furthermore, Moracin D increased sub G1 population; cleaved poly (Adenosine diphosphate (ADP-ribose)) polymerase (PARP); activated cysteine aspartyl-specific protease 3 (caspase 3); and attenuated the expression of c-Myc, cyclin D1, B-cell lymphoma 2 (Bcl-2), and X-linked inhibitor of apoptosis protein (XIAP) in MDA-MB231 cells. Of note, Moracin D reduced expression of Forkhead box M1 (FOXM1), β-catenin, Wnt3a, and upregulated glycogen synthase kinase 3 beta (GSK3β) on Tyr216 along with disturbed binding of FOXM1 with β-catenin in MDA-MB-231 cells. Conversely, GSK3β inhibitor SB216763 reversed the apoptotic ability of Moracin D to reduce expression of FOXM1, β-catenin, pro-caspase3, and pro-PARP in MDA-MB-231 cells. Overall, these findings provide novel insight that Moracin D inhibits proliferation and induces apoptosis via suppression of Wnt3a/FOXM1/β-catenin signaling and activation of caspases and GSK3β.

Circ-FOXM1 promotes the proliferation, migration and EMT process of osteosarcoma cells through FOXM1-mediated Wnt pathway activation

“…FOXM1 deubiquitinated by USP21 modulates cell cycle and paclitaxel sensitivity of basal-like breast cancer cells [ 38 ]. Repression of Wnt3a/FOXM1/β-Catenin pathway is widely involved in the apoptotic impact of moracin D in breast cancer [ 39 ]. Consistent with the report of Zhu et al [ 18 ], we verified that FOXM1 was expressed at high levels in OS cells.…”

Circ-FOXM1 Promotes Cell Proliferation, Migration and EMT Process in Osteosarcoma Through FOXM1-Mediated Wnt Pathway Activation

“…The participation of circRNAs in ceRNA network is universally known to be related to the posttranscriptional regulation of target mRNAs [34][35][36]. The ceRNA mechanism refers to that circRNA can act as a ceRNA to sponge miRNA, so as to regulate mRNA expression [24].…”

Moracin D induces apoptosis in prostate cancer cells via activation of PPAR gamma/PKC delta and inhibition of PKC alpha

“…Herein, Moracin D decreased phosphorylation of NF-κB, ERK, and AKT but not p38 and JNK, in DU145 cells (Figure 4c,d). (Hwang et al, 2018), antitumor mechanisms of Moracin D still remain unclear so far. Thus, in the current study, the underlying apoptotic mechanism of Moracin D was explored in prostate cancer cells.…”

“…Curcumin (Sha et al, 2016), rhizochalinin (Dyshlovoy et al, 2016), apigenin (Erdogan et al, 2016), and icaritin (Hu et al, 2016) showed antitumor effects in prostate cancers. In the same line, though Moracin D, a novel 2-arylbenzofuran flavonoid isolated from the Morus alba, is reported to have hypoglycemic (Basnet, Kadota, Terashima, Shimizu, & Namba, 1993), antiadipogenic (Hu et al, 2016), and antitumor effect only in breast cancer (Hwang et al, 2018), biological studies with Moracin D are still in the beginning so far. Thus, in the current study, the antitumor mechanism of Moracin D was explored in prostate cancer cells in association with PPAR-γ-/PKC-δ-related signaling.…”