Mechanism of metastasis suppression by luteolin in breast cancer

Figures & data

Figure 1 Chemical structure of luteolin.

Table 1 Effect of luteolin on breast cancer at a glance

Cell line	Target	Effect	Reference
MDA-MB-435, MDA-MB-231*	VEGF/VEGFR-2	Decreased VEGF, cell migration, lung-nodule formation	^Citation14
MDA-MB-231, MCF7	Notch1, VEGF, MMP-2, MMP-9	Reduced invasion potential, Notch1, VEGF, and MMPs	^Citation15
T47D, BT-474	VEGF	Suppressed progestin-induced VEGF, blood vessel, stem-like properties, and tumorigenicity	^Citation16
MDA-MB-231, BT549	Wnt/β-catenin	Decreased β-catenin, Snail, Slug, vimentin, N-cadherin, and lung-tumor nodules	^Citation18
MCF7	MMP-9, IL-8, ERK	Decreased TPA-induced migration and invasion, MMP-9, IL-8, and ERK, NF-κB, and c-Jun activity	^Citation27
MCF7	AEG-1, MMP-2	Decreased cell migration and AEG-1 and MMP-2 protein levels	^Citation29
MDA-MB-231, SUM-149	RSK/YB1, Notch4	Inhibited RSK, Notch4, pGSK-3β, and YB-1 activation	^Citation39
MDA-MB-231	EGFR/MAPK	Decreased Akt, PLK1, cyclin B1, cyclin A, CDK2, Bcl-xL, and EGF-induced pEGFR; increased p21 and Bax	^Citation61
MCF7*	p21, p38, p53, cyclin D1	Induced p21, p38, and p53; reduced cyclin D1	^Citation62
MDA-MB-453	HER2, Akt, S6K	Decreased HER2 and p21, upregulated p27; increased p21, transient suppression of Akt except at highest dose	^Citation63
MDA-MB-453	HER2	Decreased HER2/neu protein expression	^Citation74
MCF7	DR5, Bcl-2	Enhanced DR5 and caspase 8/9/3, inactivated PARP, increased Bax, and inhibited Bcl-2	^Citation76
MCF7	EGFR	Suppressed EGF-induced pEGFR, Akt, pErk1/2, pSTAT3	^Citation84
MDA-MB-231	STAT3	Paclitaxel combined therapy increased apoptosis, inhibited STAT3, increased FAS expression	^Citation87
MCF7	IGFR, Akt, ERα	Decreased IGF-induced pIGFR, Akt, and ERα, but not ERK; silencing ERα mitigated effects.	^Citation91
MCF7	PKL1	E2 combination therapy blocked PKL1 expression	^Citation96
MCF7	Akt	Reduced doxorubicin-induced cytotoxicity, increased Akt and Bcl-2 protein expression	^Citation98
MDA-MB-231, HS-578T, MCF7	Akt, p53, FOXO	Increased p53 and cytochrome C; cleaved PARP, nFOXO3a, p21, and p27; inhibited cell migration, pAkt, and cFOXO3a	^Citation101
MDA-MB-231	p53	Decreased Bcl-2 mRNA expression and increased p53	^Citation102
MDA-MB-231, MCF7	Akt	Increased apoptosis, decreased Akt	^Citation105
MDA-MB-231	FAS	↓ FAS and cell viability	^Citation109
MDA-MB-231	nAChR, AKT, ERK, NFκB	Decreased nicotine-induced α9-nAChR, AKT, ERK, and NF-κB-induced α9-nAChR luciferase activity	^Citation117
MDA-MB-231, MCF7	Cyclin E2	Reestablished tamoxifen efficacy; reduced cyclin E2	^Citation119
MCF7*	MRP	GSX pump inhibition	^Citation120
MDA-MB-231	cMet	Decreased cMet levels	^Citation121
MCF7, SKBR3, MDA-MB-231	AIF, ERK, p38	Increased ERK, p38 protein, and caspase 3; cleaved PARP; decreased AIF nuclear localization	^Citation122
MCF7	Glycolysis	Reversed hypoxia-induced doxorubicin resistance	^Citation123

Note:

* Variant cell line.

Figure 2 Luteolin inhibition of receptor-mediated tumor progression.

Notes: Involvement of luteolin (green) in modifying processes necessary for metastasis. Notch activation results in removal of the intracellular domain of the membrane-bound Notch receptor, creating the NICD. NICD is blocked by luteolin through an undetermined mechanism. Wnt/β-catenin inhibits GSK3 activity upon activation. Luteolin blocks Wnt-induced phosphorylation of GSK3, and thus prevents GSK3 inhibition. Luteolin has been shown to inhibit RTK activities and their downstream effectors (see text for specific RTKs and associated effector responses). Possible outcomes for each receptor pathway are in the corresponding colored boxes. Intracellular proteins color-coded as protein kinases (blue), TCFs (gray), and other proteins (brown). Dashed line represents possible luteolin interaction.
Abbreviations: EMT, epithelial–mesenchymal transition; JAK, Janus kinase; Lu, luteolin; NICD, notch intracellular domain; RSK, ribosomal S6 kinase; RTK, receptor tyrosine kinase; TCF, transcription factor.

Figure 3 Luteolin-mediated extrinsic and intrinsic apoptosis in breast cancer.

Notes: Illustration abridging the involvement of luteolin (green) in purposed apoptotic pathways. Luteolin sensitized the DR, activated caspase 8, and induced caspase 3-mediated apoptosis. Decreased FAS activity directly or indirectly by luteolin leads to apoptosis through an unknown mechanism. Inhibition of Akt or ERK leads to increased activity in the intrinsic apoptosis pathway. Circumstantially, luteolin acts as an antioxidant or drives ROS-mediated apoptosis. Intracellular proteins color-coded as protein kinases (blue), TCFs (gray), and other proteins (brown). Dashed line represents possible luteolin interaction.
Abbreviations: DR, death receptor; Lu, luteolin; ROS, reactive oxygen species; TCFs, transcription factors.

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