Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3

被引:347
作者
Kanzawa, T
Zhang, L
Xiao, LC
Germano, IM
Kondo, Y
Kondo, S
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Unit 64, Houston, TX 77030 USA
[2] Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA
[3] Mt Sinai Sch Med, Dept Neurosurg, New York, NY 10510 USA
关键词
arsenic trioxide; autophagy; BNIP3; glioma; LC3;
D O I
10.1038/sj.onc.1208095
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Arsenic trioxide (As2O3) has shown considerable efficacy in treating hematological malignancies with induction of programmed cell death (PCD) type I, apoptosis. However, the mechanisms underlying the antitumor effect of As2O3 on solid tumors are poorly defined. Previously, we reported that As2O3 induced autophagic cell death (PCD type II) but not apoptosis in human malignant glioma cell lines. The purpose of this study was to elucidate the molecular pathway leading to autophagic cell death. In this study, we demonstrated that the cell death was accompanied by involvement of autophagy-specific marker, microtubule-associated protein light chain 3 (LC3), and damage of mitochondrial membrane integrity, but not by caspase activation. Analysis by cDNA microarray, RT-PCR, and Western blot showed that cell death members of Bcl-2 family, Bcl-2/adenovirus E1B 19-kDa- interacting protein 3 (BNIP3) and its homologue BNIP3-like (BNIP3L), were upregulated in As2O3-induced autophagic cell death. Exogenous expression of BNIP3, but not BNIP3L, induced autophagic cell death in malignant glioma cells without As2O3 treatment. When upregulation of BNIP3 induced by As2O3 was suppressed by a dominant-negative effect of the transmembrane-deleted BNIP3 (BNIP3DTM), autophagic cell death was inhibited. In contrast, BNIP3 transfection augmented As2O3-induced autophagic cell death. These results suggest that BNIP3 plays a central role in As2O3-induced autophagic cell death in malignant glioma cells. This study adds a new concept to characterize the pathways by which As2O3 acts to induce autophagic cell death in malignant glioma cells.
引用
收藏
页码:980 / 991
页数:12
相关论文
共 56 条
[1]   Arsenic trioxide induces apoptosis in neuroblastoma cell lines through the activation of caspase 3 in vitro [J].
Akao, Y ;
Nakagawa, Y ;
Akiyama, K .
FEBS LETTERS, 1999, 455 (1-2) :59-62
[2]   Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1 [J].
Albertoni, M ;
Shaw, PH ;
Nozaki, M ;
Godard, S ;
Tenan, M ;
Hamou, MF ;
Fairlie, DW ;
Breit, SN ;
Paralkar, VM ;
de Tribolet, N ;
Van Meir, EG ;
Hegi, ME .
ONCOGENE, 2002, 21 (27) :4212-4219
[3]   The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway [J].
Arico, S ;
Petiot, A ;
Bauvy, C ;
Dubbelhuis, PF ;
Meijer, AJ ;
Codogno, P ;
Ogier-Denis, E .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (38) :35243-35246
[4]   Protein phosphatase 1α is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis [J].
Ayllón, V ;
Martínez, C ;
García, A ;
Cayla, X ;
Rebollo, A .
EMBO JOURNAL, 2000, 19 (10) :2237-2246
[5]   ADENOVIRUS-E1B 19-KDA AND BCL-2 PROTEINS INTERACT WITH A COMMON SET OF CELLULAR PROTEINS [J].
BOYD, JM ;
MALSTROM, S ;
SUBRAMANIAN, T ;
VENKATESH, LK ;
SCHAEPER, U ;
ELANGOVAN, B ;
DSAEIPPER, C ;
CHINNADURAI, G .
CELL, 1994, 79 (02) :341-351
[6]  
Brandes A A, 2001, Expert Rev Anticancer Ther, V1, P357, DOI 10.1586/14737140.1.3.357
[7]   Malignant gliomas. [J].
Burton E.C. ;
Prados M.D. .
Current Treatment Options in Oncology, 2000, 1 (5) :459-468
[8]   The E1B 19K Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis [J].
Chen, G ;
Ray, R ;
Dubik, D ;
Shi, LF ;
Cizeau, J ;
Bleackley, RC ;
Saxena, S ;
Gietz, RD ;
Greenberg, AH .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (12) :1975-1983
[9]  
Chen GQ, 1996, BLOOD, V88, P1052
[10]  
Clifford JL, 2003, MOL CANCER THER, V2, P453