Luteolin inhibits angiogenesis of the M2‑like TAMs via the downregulation of hypoxia inducible factor‑1α and the STAT3 signalling pathway under hypoxia

Abstract

The imbalance between angiogenic inducers and inhibitors appears to be a critical factor in tumour pathogenesis. Angiogenesis serves a key role in the occurrence, invasion and metastasis of tumours. Macrophages are a major cellular component of human and rodent tumours, where they are usually termed tumour‑associated macrophages (TAMs). In malignant tumours, TAMs tend to resemble alternatively activated macrophages (M2‑like), promote TA angiogenesis, strengthen tumour migration and invasive abilities, and simultaneously inhibit antitumor immune responses. In our previous study, luteolin, commonly found in a wide variety of plants, had a strong antitumor effect under normoxia; however, it is unknown whether luteolin serves a similar role under hypoxia. In the present study, cobalt chloride (CoCl2) was used to simulate hypoxia. Hypoxia‑inducible factor‑1α (HIF‑1α), which is difficult to detect under normoxic conditions, was significantly increased. Additionally, vascular endothelial growth factor (VEGF) was also significantly increased in response to CoCl2 treatment. Subsequently, luteolin was applied with CoCl2 to examine the effects of luteolin. Luteolin decreased the expression of VEGF and matrix metalloproteinase‑9, which promote angiogenesis. In addition, luteolin also suppressed the activation of HIF‑1 and phosphorylated‑signal transducer and activator of transcription 3 (STAT3) signalling, particularly within the M2‑like TAMs. The results of the present study provide novel evidence that luteolin, under hypoxic conditions, has a strong anticancer effect via the HIF‑1α and STAT3 signalling pathways.

Flavonoids Targeting HIF-1: Implications on Cancer Metabolism

“…Common flavone luteolin suppressed HIF-1 activation within M2-like tumor-associated macrophages (TAMs) under hypoxic conditions [ 138 ].…”

Potential Molecular Mechanisms of Plantain in the Treatment of Gout and Hyperuricemia Based on Network Pharmacology

“…Studies have shown that plantain can inhibit the expression of HIF-1 α and VEGF and the phosphorylation of protein kinase B (Akt) and downregulate the gene expression of TNF- α and IL-1 β and the activation of NF- κ B to treat diabetic retinal injury [ 51 ]. The compounds dinatin [ 52 ], baicalein [ 53 ], baicalin [ 54 ], and luteolin [ 55 ] have been shown to reduce HIF-1 level. Therefore, HIF-1 α signaling pathway may be the pathway of plantain in the treatment of gouty arthritis, and the specific mechanism and pathway need to be further verified.…”

“…Luteolin has high anti-inflammatory activity and can effectively inhibit the expression of NLRP3 by inhibiting IL-17A signal in enteritis tissue [ 100 ]. Luteolin can inhibit the activation of HIF-1 and STAT3 signal and reduce the expression of VEGF and MMP-9 to play anticancer role [ 55 ]. It can inhibit the levels of TNF- α , IL-6, IL-1 β , IL-17, membrane cation-selective receptor channels (P2X4), nucleotide oligomerization domain-like receptor protein 1 (NLRP1), apoptosis-associated speck-like protein containing CARD (ASC), and caspase-1p10 in RA rats induced by Freund's complete adjuvant and reduce the infiltration of inflammatory cells and synovial hyperplasia [ 45 ].…”

LncRNA MALAT1 Promotes STAT3-Mediated Endothelial Inflammation by Counteracting the Function of miR-590

“…STAT3 is a well-characterized inflammatory transcription factor which can be activated by a wide range of extracellular or intracellular stimuli, including IL-6 family members IL-6, IL-11, IL-27, leukemia inhibitory factor, IL-10 family members IL-10, IL-22, epidermal growth factor, VEGF, or environmental stimuli such as hypoxia or glucose deprivation [Carlsson et al, 2018;Fang et al, 2018]. Many evidences have indicated that overactivation of STAT3 signaling is associated with the initiation or progression of endothelial inflammation.…”