Luteolin inhibits triple-negative breast cancer by inducing apoptosis and autophagy through SGK1-FOXO3a-BNIP3 signaling

Abstract

Background: Triple-negative breast cancer (TNBC) is one of the most prominent neoplasm disorders and lacks efficacious treatments yet. Luteolin (3′,4′,5,7-tetrahydroxyflavone), a natural flavonoid commonly presented in plants, has been reported to delay the progression of TNBC. However, the precise mechanism is still elusive. We aimed to elucidate the inhibition and molecular regulation mechanism of luteolin on TNBC.Methods: The effects of luteolin on the biological functions of TNBC cells were first evaluated using the corresponding assays for cell counting kit-8 assay, flow cytometry, wound-healing assay, and transwell migration assay, respectively. The mechanism of luteolin on TNBC cells was then analyzed by RNA sequencing and verified by RT-qPCR, Western blot, transmission electron microscopy, etc. Finally, in vivo mouse tumor models were constructed to further confirm the effects of luteolin on TNBC.Results: Luteolin dramatically suppressed cell proliferation, invasion, and migration while favoring cell apoptosis in a dose- and time-dependent manner. In TNBC cells treated with luteolin, SGK1 and AKT3 were significantly downregulated while their downstream gene BNIP3 was upregulated. According to the results of 3D modeling, the direct binding of luteolin to SGK1 was superior to that of AKT3. The inhibition of SGK1 promoted FOXO3a translocation into the nucleus and led to the transcription of BNIP3 both in vitro and in vivo, eventually facilitating the interaction between BNIP3 and apoptosis and autophagy protein. Furthermore, the upregulation of SGK1, induced by luteolin, attenuated the apoptosis and autophagy of the TNBC.Conclusion: Luteolin inhibits TNBC by inducing apoptosis and autophagy through SGK1-FOXO3a-BNIP3 signaling.

Exploiting Nanotechnology for Drug Delivery: Advancing the Anti-Cancer Effects of Autophagy-Modulating Compounds in Traditional Chinese Medicine

“…115 To identify potential targets for LUT therapy, a recent study utilized advanced techniques such as RNA sequencing and molecular docking programs. 116…”

“…The following Table 1 summarizes the autophagy-modulating ingredients of TCM and their nanoformulations. EVO and CQ-loaded liposomes [169] FA-targeted EVO-loaded nano-micelles [170] TPP-targeted Dex-ss-SPCL NPs load DOX and EVO [171] pH-triggered EVO-loaded DUCNPs with in vivo tumour imaging function [172] EGFR-targeted EVO-loaded NCA NPs with in vivo tumour imaging function [173] Icariin PI3K/AKT/mTOR miR-7/mTOR/ SREBP1 [108,110] AEAA-targeted ICA-loaded PLGA-PEG NPs with ICD-induced function [147] ICA and pyropheophorbide-a self-assembled NPs combining ROS-induced, autophagy-induced, and PDT function [174] Thermosensitive liposome loading ICA [148] iRGD-modified ICA-loaded DSPE-PEG NPs encapsulated by RBC membrane [175] Luteolin SGK1/FOXO3a/ BNIP3 PI3K/AKT/mTOR [116,176] FA-targeted LUT-loaded PEG-PCL NPs [149] ROS-triggered LUT-loaded PPS-PEG NPs [177] ROS-triggered and FA-targeted loaded LUT DSPE-PEG NPs [178] Epigallocatechin gallate PI3K/AKT/mTOR JAK/STAT3 Ras/MEK/ERK HSP90 related pathways [117,[119][120][121]179,180] HA-targeted EGCG NPs with ROS-induced and ferroptosis-induced function [181] Manganese carbonyl and dendritic mesoporous silicon NPs loading EGCG with PTT function [182] PD-L1 targeted fluorinated-coordinative-EGCG loaded Zn2+ NPs [183] FA-targeted EGCG-loaded liposomes [184] UV blocker ZnO and the antioxidants lycopene and olive oil copolymer NPs loaded EGCG [185] α SKN and CQ-loaded liposomes combining autophagy-induced and ICD-induced function [58] Fe-Shikonin metal-phenolic networks covering CpG ODN-loaded aluminum hydroxyphosphate nanoparticles loading SKN as in situ nano vaccines inducing ICD, ferroptosis, and necroptosis [191] Transferrin-targeted SKN and JQ1 loaded with ICD-induced function [192] (Continued)…”

Luteolin: A promising multifunctional natural flavonoid for human diseases

“…In vivo (female BALB/c mice) and in vitro studies by Wu et al suggested that LUT regulated the SGK1‐FOXO3a‐BNIP3 pathway, inducing apoptosis and autophagy in TNBC cells. The specific mechanism of action was through the inhibition of FOXO1a phosphorylation and augmentation of BNIP3 expression (Wu, Lin, et al, 2023). It is worth noting that breast cancer often appeared in hypoxic areas, where hypoxia was often directly related to invasion and metastasis.…”