The inhibition of hypoxia‐induced angiogenesis and metastasis by cinnamaldehyde is mediated by decreasing HIF‐1α protein synthesis via PI3K/Akt pathway

Abstract

Tumor hypoxia is positively correlated with tumor aggressiveness and hence is a negative prognostic factor in cancer. As normal cells usually do not experience such low oxygen levels, hypoxic cell signaling has attracted significant attention for the development of tumor-selective treatment strategies. In response to hypoxia, the master transcriptional regulator, HIF-1α plays central role in cellular adaptation by transactivating several crucial downstream target genes, which are involved in angiogenesis, metastasis, and EMT. In this study, we investigated the effect of cinnamaldehyde (CA), the main active ingredient of Cinnamon cassia bark extract, on hypoxia-induced angiogenesis and metastasis. The study in vitro comprised two cell lines, viz, sarcoma 180 and B16F10 melanoma, which were further confirmed in their respective transplantable in vivo models. Results show that CA administration inhibited tumor angiogenesis, EMT, and metastasis. At the molecular level, this was accompanied by a reduction in VEGF secretion, VEGF receptor (FLK) phosphorylation, matrix metalloproteinase (MMP) expression, and activity as well as a reduction in the EMT-related factors TWIST and ZEB1. Next, we focused our study particularly on the modulation of HIF-1 α by CA, which revealed that CA decreased HIF-1 α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the PI3/Akt/m-TOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CA both in vitro and in vivo. Thus, it can be concluded that CA decreased angiogenesis and metastasis in tumor cells by inhibiting HIF-1α protein accumulation probably by targeting the PI3/Akt/mTOR pathway. © 2019 BioFactors, 45(3):401-415, 2019

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

“…In addition, AKT activation induces the expression of high levels of HIF-1, an important regulator of angiogenesis that can upregulate the expression of VEGF and other angiogenic factors, thereby promoting angiogenesis. HIF-1 affects vascular endothelial cells through the following mechanisms of action: (1) promoting the migration and proliferation of endothelial cells; (2) increasing vascular permeability, plasma protein exosmosis, and cellulose scaffold formation to help vascular endothelial cells migrate and provide support for vascular growth; and (3) activating the proteolytic enzyme system, degrading the extracellular matrix and promoting angiogenesis [109][110][111][112].…”

Inflammation-Mediated Angiogenesis in Ischemic Stroke

“…HIF-1α, thereby regulating VEGF expression (Patra et al, 2019), which is known to enhance angiogenesis after IS. In addition, epidermal growth factor (EGF) exerts neuroprotective effects on cerebral ischemia via activating the EGF receptor (EGFR), which also contributes to the activation of the PI3K/AKT/mTOR pathway and elevated HIF-1α (Karar and Maity, 2011).…”

Cinnamaldehyde protects against oxidative stress and inhibits the TNF‑α‑induced inflammatory response in human umbilical vein endothelial cells

“…To examine the anti-inflammatory effects of CA in vivo, Sprague-Dawley rats were pre-treated with CA and then exposed to LPS, as described in the Materials and methods section. Various concentrations (20 mg to 100 mg/kg) of CA have been applied to tumor and inflammatory animal models (24,25). Based on previous studies, the present study examined the anti-inflammatory effects of CA (20 and 50 mg/kg) in an animal model.…”