title: Anti-cancer fatty-acid derivative induces autophagic cell death through modulation of PKM isoform expression profile mediated by bcr-abl in chronic myeloid leukemia.
abstract: The fusion gene bcr-abl develops chronic myeloid leukemia (CML), and stimulates PI3K/Akt/mTOR signaling, leading to impaired autophagy. PI3K/Akt/mTOR signaling also plays an important role in cell metabolism. The Warburg effect is a well-recognized hallmark of cancer energy metabolism, and is regulated by the mTOR/c-Myc/hnRNP/PKM signaling cascade. To develop a new strategy for the treatment of CML, we investigated the associations among bcr-abl, the cascade related to cancer energy metabolism, and autophagy induced by a fatty-acid derivative that we had previously reported as being an autophagy inducer. Here we report that a fatty-acid derivative, AIC-47, induced transcriptional repression of the bcr-abl gene and modulated the expression profile of PKM isoforms, resulting in autophagic cell death. We show that c-Myc functioned as a transcriptional activator of bcr-abl, and regulated the hnRNP/PKM cascade. AIC-47, acting through the PPARγ/β-catenin pathway, induced down-regulation of c-Myc, leading to the disruption of the bcr-abl/mTOR/hnRNP signaling pathway, and switching of the expression of PKM2 to PKM1. This switching caused autophagic cell death through an increase in the ROS level. Our findings suggest that AIC-47 induced autophagic cell death through the PPARγ/β-catenin/bcr-abl/mTOR/hnRNP/PKM cascade.
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors: Haruka
authors: H
authors: Shinohara
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors: Kohei
authors: K
authors: Taniguchi
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors: Minami
authors: M
authors: Kumazaki
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors: Nami
authors: N
authors: Yamada
authors: Department of Anatomy and Biology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 596-8686, Japan.
authors: Yuko
authors: Y
authors: Ito
authors: Department of Anatomy and Biology, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 596-8686, Japan.
authors: Yoshinori
authors: Y
authors: Otsuki
authors: Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors: Bunji
authors: B
authors: Uno
authors: Department of Hematology and Oncology, Nagoya University Graduate school of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors: Fumihiko
authors: F
authors: Hayakawa
authors: Division of Blood Transfusion/Division of Oncology and Hematology, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
authors: Yosuke
authors: Y
authors: Minami
authors: National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Nagoya, 460-0001, Japan.
authors: Tomoki
authors: T
authors: Naoe
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address: yakao@gifu-u.ac.jp.
authors: Yukihiro
authors: Y
authors: Akao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D005227:Fatty Acids; D016044:Fusion Proteins, bcr-abl; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D007527:Isoenzymes; D008565:Membrane Proteins; D047495:PPAR gamma; D016271:Proto-Oncogene Proteins c-myc; D011770:Pyruvate Kinase; D058570:TOR Serine-Threonine Kinases; D013963:Thyroid Hormones; D051176:beta Catenin; D000097810:Thyroid Hormone-Binding Proteins; C495270:CTNNB1 protein, human; C489427:MYC protein, human; C406060:abl-bcr fusion protein, human; C546842:MTOR protein, human
keywords: Autophagy; Bcr-abl; Cell death; Fatty-acid derivative; Warburg effect