title: 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.
authors.affiliation: 1] Department of Cancer Pharmacology, Indian Institute of Integrative Medicine, Canal Road Jammu, Jammu and Kashmir 180001, India [2] Academy of Scientific and Innovative Research (AcSIR), New Delhi 110001, India.
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: S K
authors.initials: SK
authors.lastname: Guru
authors.forename: A S
authors.initials: AS
authors.lastname: Pathania
authors.forename: A
authors.initials: A
authors.lastname: Kumar
authors.forename: S
authors.initials: S
authors.lastname: Bhushan
authors.forename: F
authors.initials: F
authors.lastname: Malik
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; C584245:Ery5 compound; D017705:Lignans; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D010636:Phenols; D042461:Vascular Endothelial Growth Factor A; C005498:magnolol; D003035:Cobalt; D040301:Vascular Endothelial Growth Factor Receptor-2; C018021:cobaltous chloride