title: Her2 oncogene transformation enhances 5-aminolevulinic acid-mediated protoporphyrin IX production and photodynamic therapy response.
abstract: Enhanced protoporphyrin IX (PpIX) production in tumors derived from the administration of 5-aminolevulinic acid (ALA) enables the use of ALA as a prodrug for photodynamic therapy (PDT) and fluorescence-guided tumor resection. Although ALA has been successfully used in the clinic, the mechanism underlying enhanced ALA-induced PpIX production in tumors is not well understood. Human epidermal growth receptor 2 (Her2, Neu, ErbB2) is a driver oncogene in human cancers, particularly breast cancers. Here we showed that, in addition to activating Her2/Neu cell signaling, inducing epithelial-mesenchymal transition and upregulating glycolytic enzymes, transfection of NeuT (a mutated Her2/Neu) oncogene in MCF10A human breast epithelial cells significantly enhanced ALA-induced PpIX fluorescence by elevating some enzymes involved in PpIX biosynthesis. Furthermore, NeuT-transformed and vector control cells exhibited drastic differences in the intracellular localization of PpIX, either produced endogenously from ALA or applied exogenously. In vector control cells, PpIX displayed a cell contact-dependent membrane localization at high cell densities and increased mitochondrial localization at low cell densities. In contrast, no predominant membrane localization of PpIX was observed in NeuT cells and ALA-induced PpIX showed a consistent mitochondrial localization regardless of cell density. PDT with ALA caused significantly more decrease in cell viability in NeuT cells than in vector cells. Our data demonstrate that NeuT oncogene transformation enhanced ALA-induced PpIX production and altered PpIX intracellular localization, rendering NeuT-transformed cells increased response to ALA-mediated PDT. These results support the use of ALA for imaging and photodynamic targeting Her2/Neu-positive tumors.
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of The Sciences, Philadelphia, Pennsylvania, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of The Sciences, Philadelphia, Pennsylvania, USA.
authors.forename: Pratheeba
authors.initials: P
authors.lastname: Palasuberniam
authors.affiliation: Department of Biological Sciences, Misher College of Arts and Sciences, University of The Sciences, Philadelphia, Pennsylvania, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Myers
authors.affiliation: Key Laboratory of Tianjin Radiation and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Tianjin, China.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of The Sciences, Philadelphia, Pennsylvania, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006418:Heme / Q000737:chemistry; D006801:Humans; D007982:Levulinic Acids / Q000008:administration & dosage*; D018613:Microscopy, Confocal; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000008:administration & dosage; D011524:Protoporphyrins / Q000737:chemistry*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000622:Aminolevulinic Acid
chemical_list: D006418:Heme; D007982:Levulinic Acids; D017319:Photosensitizing Agents; D011524:Protoporphyrins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000622:Aminolevulinic Acid; C028025:protoporphyrin IX; C508053:ERBB2 protein, human
keywords: aminolevulinic acid (ALA); heme biosynthesis; human epidermal growth receptor 2 (Her2); photodynamic therapy (PDT); protoporphyrin IX (PpIX)