title: Structural requirements within protoporphyrin IX in the inhibition of heat shock protein 90.
abstract: Porphyrins are used for photodynamic therapy for their light-absorbing properties, and some of them were approved for the treatment of certain types of cancers. Porphyrins prevent activation of hypoxia inducible factor-1α (HIF-1α) by inhibiting heat shock protein 90 (HSP90). This study investigated the structural requirements within protoporphyrin IX (PPIX) for the inhibition of HSP90 activity. In HCT116, HT29 and DLD-1 cells, PPIX treatment directly hindered the binding between HSP90 and HIF-1α; PPIX treatment inhibited the chaperone activity of HSP90, accelerating protein degradation of HIF-1α. In addition, PPIX treatment suppressed cancer cell migration, endothelial cell tube formation, and aortic ring sprouting, being consistent with its anti-tumor and anti-angiogenic activities. In silico analysis, molecular docking model indicated that a tetrapyrrole macrocycle and two propionate chains within PPIX are necessary for the binding to the adenosine triphosphate (ATP)-binding pocket of HSP90. The predicted structural requirement was verified by the differential inhibitory effects of PPIX analogs, or the precursor of PPIX, on HIF-1α; compounds lacking either the tetrapyrrole macrocycle or the propionate chains were inactive. Our results show that a tetrapyrrole macrocycle and two attached propionate chains in PPIX coordinately interact with the ATP-binding pocket of HSP90, offering structural information on the inhibitory effect of porphyrins on angiogenesis.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Woo Hyung
authors.initials: WH
authors.lastname: Lee
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Chaemin
authors.initials: C
authors.lastname: Lim
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D015151:Immunoblotting; D008958:Models, Molecular; D016133:Polymerase Chain Reaction; D011485:Protein Binding / Q000187:drug effects; D011524:Protoporphyrins / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011524:Protoporphyrins; C028025:protoporphyrin IX