title: Genistein-induced apoptosis via Akt signaling pathway in anaplastic large-cell lymphoma.
abstract: More than half of anaplastic large-cell lymphoma (ALCL) are associated with chromosomal translocation t(2;5)(p23;q35) that leads to the expression of nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncoprotein. NPM-ALK activates the antiapoptotic phosphatidylinositol-3 kinase/Akt (PI3K/Akt) signaling pathway, which plays a critical role in cell survival and apoptosis. Inhibition of the PI3K/Akt pathway has been considered as a therapeutic target for cancer where PI3K/Akt activation is a causative factor. Genistein, a natural isoflavonoid found in soy products, has been shown to inhibit cell growth and induce apoptosis in a wide variety of cell lines. Here, we demonstrated that treatment of two t(2;5) ALCL cell lines, SUDHL-1 and Karpas299, with genistein induced apoptosis in a time- and dose-dependent manner. Concurrently, these cells exhibited a decrease in Akt protein levels and subsequent downregulation of Akt activity (Akt phosphorylation). Furthermore, genistein treatment induced mitochondrial membrane potential change, caspase-3 activation and PARP cleavage. From these results, we conclude that inhibition of the Akt signaling pathway and induction of apoptosis by genistein could be used as a new treatment modality for the prevention and/or treatment of t(2;5) ALCL and other hematopoietic malignancies.
authors.affiliation: Department of Pathology and Tumor Immunity, Medical Research Center and Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-779, Korea.
authors.forename: Sung-Shin
authors.initials: SS
authors.lastname: Park
authors.forename: Yong-Nyun
authors.initials: YN
authors.lastname: Kim
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
authors.forename: Young A
authors.initials: YA
authors.lastname: Kim
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Heejung
authors.initials: H
authors.lastname: Kim
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D019833:Genistein; D011065:Poly(ADP-ribose) Polymerases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases