Autophagy triggered by magnolol derivative negatively regulates angiogenesis

Abstract

Angiogenesis has a key role in the tumor progression and metastasis; targeting endothelial cell proliferation has emerged as a promising therapeutic strategy for the prevention of cancer. Previous studies have revealed a complex association between the process of angiogenesis and autophagy and its outcome on tumorigenesis. Autophagy, also known as type-II cell death, has been identified as an alternative way of cell killing in apoptotic-resistant cancer cells. However, its involvement in chemoresistance and tumor promotion is also well known. In this study, we used a derivate of natural product magnolol (Ery5), a potent autophagy inducer, to study the association between the autophagy and angiogenesis in both in vitro and in vivo model system. We found that the robust autophagy triggered by Ery5, inhibited angiogenesis and caused cell death independent of the apoptosis in human umbilical cord vein endothelial cells and PC-3 cells. Ery5 induced autophagy effectively inhibited cell proliferation, migration, invasion and tube formation. We further demonstrated that Ery5-mediated autophagy and subsequent inhibition of angiogenesis was reversed when autophagy was inhibited through 3-methyl adenine and knocking down of key autophagy proteins ATG7 and microtubule-associated protein light chain 3. While evaluating the negative regulation of autophagy on angiogenesis, it was interesting to find that angiogenic environment produced by the treatment of VEGF and CoCl2 remarkably downregulated the autophagy and autophagic cell death induced by Ery5. These studies, while disclosing the vital role of autophagy in the regulation of angiogenesis, also suggest that the potent modulators of autophagy can lead to the development of effective therapeutics in apoptosis-resistant cancer.

Endorepellin-evoked Autophagy Contributes to Angiostasis

“…Despite recent progress, the functional role of autophagy remains unclear in many biological contexts, particularly in angiogenesis, where its role remains controversial (58,59). Endorepellin, the C-terminal domain of perlecan, induces autophagy in endothelial cells (47).…”

Metabolic regulation of magnolol on the nuclear receptor, liver X receptor

“…Numerous studies have investigated the pharmacological effects of magnolol, of which a number have been demonstrated, including the inhibition of inflammation to protect endothelial cells from damage, relieving acute inflammatory pain, inhibiting cellular mutation by suppressing mutant enzyme activity, and increasing the combination degree of tranquilizers and the γ-aminobutyric acid (GABA) receptor by increasing the expression of the GABA receptor; thus, magnolol ultimately achieves central sedative and anxiolytic effects (14)(15)(16). In addition, magnolol has been shown to inhibit skin photoaging by constraining the nuclear transcription factor, nuclear factor-κB (17).…”

Anticancer activity of a novel quinazolinone-chalcone derivative through cell cycle arrest in pancreatic cancer cell line

“…Cells were thereafter incubated with 0.5% crystal violet for 30 min. Images were taken by digital camera [19] .…”