title: Autophagy and autophagic cell death are next targets for elimination of the resistance to tyrosine kinase inhibitors.
abstract: Autophagy, a cellular degradation system has been demonstrated in some hematopoietic malignant cell lines, but there is much still remaining to be known about its role and the mechanisms. We observed the excessive autophagy in chronic myelogenous leukemia (CML) cell line, K562, associated with treatment of 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which can induce K562 cells to differentiate into megakaryocytic lineage. Confocal microscopic analysis demonstrated that autophagic cells did not express a megakaryocyte marker, the CD41 molecule, indicating that the autophagy was independent of megakaryocytic differentiation. After remarkable autophagic degradation, the cells finally underwent autophagic cell death (APCD). On the other hand, a block of TPA-induced autophagy by chloroquine rapidly promoted cell death that was not APCD. This result suggested that autophagy regulated two mechanisms in K562 cells: both the cell survival system and APCD. To confirm that autophagy regulates the cell survival system in K562 cells, imatinib was used to induce cell death in K562 cells. Autophagy has not been considered during imatinib treatment; nonetheless, co-treatment with imatinib and chloroquine markedly enhanced imatinib-induced cell death, compared to K562 cells treated only with imatinib. Furthermore, imatinib-resistant cell lines, BaF3/T315I and BaF3/E255K, also underwent cell death by co-treatment with imatinib and chloroquine. From these data, we concluded that autophagy is deeply related to the cell survival system and that inhibition of autophagy accelerates TPA- or imatinib-induced cell death. The block of autophagy could be a new strategy in the treatment of CML.
authors.affiliation: Department of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mishima
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Terui
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.forename: Akiko
authors.initials: A
authors.lastname: Taniyama
authors.forename: Ryoko
authors.initials: R
authors.lastname: Kuniyoshi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takizawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Hatake
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D013755:Tetradecanoylphorbol Acetate