Hispidulin, a small flavonoid molecule, suppresses the angiogenesis and growth of human pancreatic cancer by targeting vascular endothelial growth factor receptor 2‐mediated PI3K/Akt/mTOR signaling pathway

Abstract

Hispidulin, an active component from Artemisia vestita, a traditional Tibetan medicinal plant, has been shown to possess anti-inflammatory and anti-oxidative activities. However, the functional role of hispidulin on tumor growth and angiogenesis has not been elucidated. We found that hispidulin significantly inhibited human pancreatic tumor growth in xenograft mice when s.c. treated at a dosage of 20 mg/kg daily, and this effect was accompanied with a potent inhibition on angiogenesis. When examining the cytotoxicity of hispidulin on HUVECs and pancreatic cancer cells in vitro, we found that HUVECs were more susceptible to the treatment, suggesting angiogenesis might be the primary target of hispidulin. Our results further showed that hispidulin inhibited vascular endothelial growth factor (VEGF)-induced cell migration, invasion, and capillary-like structure formation of HUVECs in a dose-dependent manner. In ex vivo and in vivo angiogenesis assays, we showed that hispidulin suppressed VEGF-induced microvessel sprouting of rat aortic rings and corneal neovascularization in C57/BL6 mice. To understand the underlying molecular basis, we next examined the effects of hispidulin on different molecular components in treated HUVECs, and found that hispidulin suppressed the VEGF-triggered activation of VEGF receptor 2, PI3K, Akt, mTOR, and ribosomal protein S6 kinase, but had little effect on focal adhesion kinase or extracellular signal-regulated kinase at an effective concentration. Taken together, our results indicate that hispidulin targets the VEGF receptor 2-mediated PI3K/Akt/mTOR signaling pathway in endothelial cells, leading to the suppression of pancreatic tumor growth and angiogenesis.

Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway

“…The mTOR kinase exists as a component of two distinct protein complexes: the mTORC1 complex phosphorylates substrates S6K at Thr389 and EIF4E at Ser209, while the mTORC2 complex itself phosphorylates Akt at Ser473 [42]. Based on these findings, the PI 3 K/Akt/mTOR pathway is believed to be a promising therapeutic target for the treatment of cancer, and small molecules that inhibit one or more of these kinases are now being introduced into the clinic and may have some activity [43,44]. For example, TGF-β increased COX-2 levels and PGE 2 secretion in prostate cancer cells which, in turn, mediate TGF-β effects on cell migration and invasion through the activation of PI 3 K/AKT/mTOR pathway [45].…”

Honokiol Inhibits Vascular Vessel Formation of Mouse Embryonic Stem Cell-Derived Endothelial Cells via the Suppression of PECAM and MAPK/mTOR Signaling Pathway

“…In angiogenesis, MAP kinases are activated by various stimuli including VEGF in endothelial cells and regulate multiple critical steps by phosphorylating different downstream substrates such as mTOR [45]. MAPK/mTOR signaling is one of the critical molecular events during growth, survival and migration in VEGF-induced angiogenesis of vascular endothelial cells [46,47]. To determine whether the anti-angiogenic activity of honokiol is associated with the modulation of MAPK/mTOR signaling pathways the expression of MAPK/mTOR signaling molecules was determined in the EB-derived endothelial cells.…”

Effect of bortezomib on migration and invasion in cervical carcinoma HeLa cell

“…mTOR is an atypical serine/threonine protein kinase comprised by more than 2000 amino acids, which can make threonine phosphorylation and is also one member of PI3K family. Akt/ mTOR signaling pathway activation is closely related with development of metastasis in breast cancer [17], melanoma [18,19], pancreatic cancer [20,21], cervical cancer [3,4]. In up to 95% of cervical cancer tissue, there is mTOR signaling pathway activation which plays an important role in the development of cervical cancer [22].…”