title: Appropriate modulation of autophagy sensitizes malignant peripheral nerve sheath tumor cells to treatment with imatinib mesylate.
abstract: Malignant peripheral nerve sheath tumor (MPNST), very rare in childhood, is a highly aggressive soft-tissue tumor. We experienced a case of a 7-year-old boy with MPNST who was treated with imatinib mesylate (imatinib) after the identification of platelet-derived growth factor receptor expression in his tumor. We were unable to observe clinical benefits of imatinib in this patient. Therefore, cellular reactions of imatinib were investigated in vitro using 3 MPNST cell lines. Imatinib induced cytotoxicity in vitro with variable IC50 values (11.7 to >30 μM). Induction of apoptosis was not a pivotal mechanism in the inhibitory effects. We found that the treatment of MPNST cell lines with imatinib induced autophagy. Suppression of the initiation of autophagy by 3-methyladenine or small interfering RNA (siRNA) against beclin-1 attenuated the imatinib-mediated cytotoxicity. In contrast, blocking the formation of autophagosomes or the development of autolysosomes using siRNA against microtubule-associated protein light chain 3B, bafilomycin A1, chloroquine, or an MEK1/2 inhibitor (U0126) enhanced the imatinib-induced cytotoxicity in MPNST cells. Our data showed that the imatinib-mediated autophagy can function as a cytotoxic mechanism and that appropriate modulation of autophagy may sensitize MPNST cells to imatinib, which in turn may be a novel therapeutic strategy for MPNST.
authors.affiliation: Department of Pediatrics, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Munehiro
authors.initials: M
authors.lastname: Okano
authors.forename: Naoki
authors.initials: N
authors.lastname: Sakata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueda
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Takemura
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D001549:Benzamides / Q000627:therapeutic use*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009442:Neurilemmoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010588:Phagosomes / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D001549:Benzamides; D008565:Membrane Proteins; D010879:Piperazines; D011743:Pyrimidines; D034741:RNA, Small Interfering; C025946:3-methyladenine; D000068877:Imatinib Mesylate; D000225:Adenine