title: Cytotoxic mechanisms of panduratin A on A375 melanoma cells: A quantitative and temporal proteomics analysis.
abstract: Melanoma is a lethal form of skin cancer with rising global incidence. However, limited treatment options are available for advanced melanoma and this is further compounded by the development of resistance toward existing drugs. Panduratin A (PA), a cyclohexanyl chalcone found in Boesenbergia rotunda, was investigated for its cytotoxic potentials against human malignant melanoma A375 cells. Our initial findings revealed that mitochondrion is the primary acting site of PA on A375 cancer cells and the cytotoxic mechanisms of PA were further investigated using a temporal quantitative proteomics approach by iTRAQ 2D-LC-MS/MS. Comprehensive proteomics analysis identified 296 proteins that were significantly deregulated in PA-treated A375 cells and revealed the involvement of mitochondrial oxidative phosphorylation, secretory and ER stress pathway, and apoptosis. We further confirmed that the PA-induced apoptosis was mediated by prolonged ER stress at least in part via the PERK/eIF2α/ATF4/CHOP pathway. Pretreatment with cycloheximide, an ER stress inhibitor rescued PA-induced cell death, which was accompanied by the suppression of ER-stress-related HSPA5 and CHOP proteins. The present study provides comprehensive mechanistic insights into the cytotoxic mechanisms of PA.
authors.affiliation: Centre of Natural Products & Drug Discovery (CENAR), Department of Pharmacology, Faculty of Medicine, University of Malaya, Malaysia.
authors.forename: Siew-Li
authors.initials: SL
authors.lastname: Lai
authors.forename: Pooi-Fong
authors.initials: PF
authors.lastname: Wong
authors.forename: Teck-Kwang
authors.initials: TK
authors.lastname: Lim
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Lin
authors.forename: Mohd Rais
authors.initials: MR
authors.lastname: Mustafa
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D030521:Zingiberaceae / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047188:Chalcones; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D020543:Proteome; C482884:panduratin A
keywords: Biomedicine; Cytotoxic mechanism; ER stress; Panduratin A; iTRAQ