This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Daido, S. Articles by Kondo, S. Search for Related Content PubMed PubMed Citation Articles by Daido, S. Articles by Kondo, S.

Pivotal Role of the Cell Death Factor BNIP3 in Ceramide-Induced Autophagic Cell Death in Malignant Glioma Cells

¹ Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, and ² Department of Cell Biology and Bioscience, The Nagahama Institute of Bioscience and Technology, Nagahama, Shiga, Japan

The sphingolipid ceramide has been recognized as an important second messenger implicated in regulating diverse signaling pathways especially for apoptosis. Very little is known, however, about the molecular mechanisms underlying nonapoptotic cell death induced by ceramide. In the present study, we first demonstrate that ceramide induces nonapoptotic cell death in malignant glioma cells. The cell death was accompanied by several specific features characteristic of autophagy: presence of numerous autophagic vacuoles in the cytoplasm, development of the acidic vesicular organelles, autophagosome membrane association of microtubule-associated protein light chain 3 (LC3), and a marked increase in expression levels of two forms of LC3 protein (LC3-I and LC3-II). We additionally demonstrate that ceramide decreases mitochondrial membrane potential and activates the transcription of death-inducing mitochondrial protein, BNIP3, resulting in increased expression levels of its mRNA and protein in malignant glioma cells. Moreover, tumor cells transfected with BNIP3 gene undergo autophagy in the absence of ceramide. These results suggest that ceramide induces autophagic cell death in malignant glioma cells via activation of BNIP3. This study adds a new concept to characterize the pathways by which ceramide acts to induce nonapoptotic autophagic cell death in malignant gliomas.

This article has been cited by other articles:

				C.-L. Chang, M.-C. Ho, P.-H. Lee, C.-Y. Hsu, W.-P. Huang, and H. Lee S1P5 is required for sphingosine 1-phosphate-induced autophagy in human prostate cancer PC-3 cells Am J Physiol Cell Physiol, August 1, 2009; 297(2): C451 - C458. [Abstract] [Full Text] [PDF]

				T.-J. Liu, D. Koul, T. LaFortune, N. Tiao, R. J. Shen, S.-M. Maira, C. Garcia-Echevrria, and W.K. A. Yung NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas Mol. Cancer Ther., August 1, 2009; 8(8): 2204 - 2210. [Abstract] [Full Text] [PDF]

				P. Giussani, L. Brioschi, R. Bassi, L. Riboni, and P. Viani Phosphatidylinositol 3-Kinase/AKT Pathway Regulates the Endoplasmic Reticulum to Golgi Traffic of Ceramide in Glioma Cells: A LINK BETWEEN LIPID SIGNALING PATHWAYS INVOLVED IN THE CONTROL OF CELL SURVIVAL J. Biol. Chem., February 20, 2009; 284(8): 5088 - 5096. [Abstract] [Full Text] [PDF]

				S. Pattingre, C. Bauvy, S. Carpentier, T. Levade, B. Levine, and P. Codogno Role of JNK1-dependent Bcl-2 Phosphorylation in Ceramide-induced Macroautophagy J. Biol. Chem., January 30, 2009; 284(5): 2719 - 2728. [Abstract] [Full Text] [PDF]

				T. J. McLoughlin, S. M. Smith, A. D. DeLong, H. Wang, T. G. Unterman, and K. A. Esser FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner Am J Physiol Cell Physiol, January 1, 2009; 297(3): C548 - C555. [Abstract] [Full Text] [PDF]

				L.-K. Sy, S.-C. Yan, C.-N. Lok, R. Y.K. Man, and C.-M. Che Timosaponin A-III Induces Autophagy Preceding Mitochondria-Mediated Apoptosis in HeLa Cancer Cells Cancer Res., December 15, 2008; 68(24): 10229 - 10237. [Abstract] [Full Text] [PDF]

				C. Bartholomeusz, D. Rosen, C. Wei, A. Kazansky, F. Yamasaki, T. Takahashi, H. Itamochi, S. Kondo, J. Liu, and N. T. Ueno PEA-15 Induces Autophagy in Human Ovarian Cancer Cells and Is Associated with Prolonged Overall Survival Cancer Res., November 15, 2008; 68(22): 9302 - 9310. [Abstract] [Full Text] [PDF]

				G. G. Guenther, E. R. Peralta, K. R. Rosales, S. Y. Wong, L. J. Siskind, and A. L. Edinger Ceramide starves cells to death by downregulating nutrient transporter proteins PNAS, November 11, 2008; 105(45): 17402 - 17407. [Abstract] [Full Text] [PDF]

				K. Nishida, O. Yamaguchi, and K. Otsu Crosstalk Between Autophagy and Apoptosis in Heart Disease Circ. Res., August 15, 2008; 103(4): 343 - 351. [Abstract] [Full Text] [PDF]

				M. Tiwari, V. K. Bajpai, A. A. Sahasrabuddhe, A. Kumar, R. A. Sinha, S. Behari, and M. M. Godbole Inhibition of N-(4-hydroxyphenyl)retinamide-induced autophagy at a lower dose enhances cell death in malignant glioma cells Carcinogenesis, March 1, 2008; 29(3): 600 - 609. [Abstract] [Full Text] [PDF]

				A Giatromanolaki, M I Koukourakis, K C Gatter, A L Harris, and E Sivridis BNIP3 expression in endometrial cancer relates to active hypoxia inducible factor 1{alpha} pathway and prognosis J. Clin. Pathol., February 1, 2008; 61(2): 217 - 220. [Abstract] [Full Text] [PDF]

				K. Fujiwara, S. Daido, A. Yamamoto, R. Kobayashi, T. Yokoyama, H. Aoki, E. Iwado, N. Shinojima, Y. Kondo, and S. Kondo Pivotal Role of the Cyclin-dependent Kinase Inhibitor p21WAF1/CIP1 in Apoptosis and Autophagy J. Biol. Chem., January 4, 2008; 283(1): 388 - 397. [Abstract] [Full Text] [PDF]

				Y. Li, Y. Wang, E. Kim, P. Beemiller, C.-Y. Wang, J. Swanson, M. You, and K.-L. Guan Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb J. Biol. Chem., December 7, 2007; 282(49): 35803 - 35813. [Abstract] [Full Text] [PDF]

				Y. Chen, E. McMillan-Ward, J. Kong, S. J. Israels, and S. B. Gibson Mitochondrial electron-transport-chain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species J. Cell Sci., December 1, 2007; 120(23): 4155 - 4166. [Abstract] [Full Text] [PDF]

				F. Lefranc, V. Facchini, and R. Kiss Proautophagic Drugs: A Novel Means to Combat Apoptosis-Resistant Cancers, with a Special Emphasis on Glioblastomas Oncologist, December 1, 2007; 12(12): 1395 - 1403. [Abstract] [Full Text] [PDF]

				N. Mizushima Autophagy: process and function Genes & Dev., November 15, 2007; 21(22): 2861 - 2873. [Abstract] [Full Text] [PDF]

				H. Aoki, E. Iwado, M. S. Eller, Y. Kondo, K. Fujiwara, G.-Z. Li, K. R. Hess, D. R. Siwak, R. Sawaya, G. B. Mills, et al. Telomere 3' overhang-specific DNA oligonucleotides induce autophagy in malignant glioma cells FASEB J, September 1, 2007; 21(11): 2918 - 2930. [Abstract] [Full Text] [PDF]

				E. Y. W. Chan, S. Kir, and S. A. Tooze siRNA Screening of the Kinome Identifies ULK1 as a Multidomain Modulator of Autophagy J. Biol. Chem., August 31, 2007; 282(35): 25464 - 25474. [Abstract] [Full Text] [PDF]

				E. H. Kim, S. Sohn, H. J. Kwon, S. U. Kim, M.-J. Kim, S.-J. Lee, and K. S. Choi Sodium Selenite Induces Superoxide-Mediated Mitochondrial Damage and Subsequent Autophagic Cell Death in Malignant Glioma Cells Cancer Res., July 1, 2007; 67(13): 6314 - 6324. [Abstract] [Full Text] [PDF]

				H. Aoki, Y. Takada, S. Kondo, R. Sawaya, B. B. Aggarwal, and Y. Kondo Evidence That Curcumin Suppresses the Growth of Malignant Gliomas in Vitro and in Vivo through Induction of Autophagy: Role of Akt and Extracellular Signal-Regulated Kinase Signaling Pathways Mol. Pharmacol., July 1, 2007; 72(1): 29 - 39. [Abstract] [Full Text] [PDF]

				Z. Zhang, X. Yang, S. Zhang, X. Ma, and J. Kong BNIP3 Upregulation and EndoG Translocation in Delayed Neuronal Death in Stroke and in Hypoxia Stroke, May 1, 2007; 38(5): 1606 - 1613. [Abstract] [Full Text] [PDF]

				U. Akar, B. Ozpolat, K. Mehta, J. Fok, Y. Kondo, and G. Lopez-Berestein Tissue Transglutaminase Inhibits Autophagy in Pancreatic Cancer Cells Mol. Cancer Res., March 1, 2007; 5(3): 241 - 249. [Abstract] [Full Text] [PDF]

				E. Y. Tan, L. Campo, C. Han, H. Turley, F. Pezzella, K. C. Gatter, A. L. Harris, and S. B. Fox BNIP3 as a Progression Marker in Primary Human Breast Cancer; Opposing Functions in In situ Versus Invasive Cancer Clin. Cancer Res., January 15, 2007; 13(2): 467 - 474. [Abstract] [Full Text] [PDF]

				A. Iwamaru, E. Iwado, S. Kondo, R. A. Newman, B. Vera, A. D. Rodriguez, and Y. Kondo Eupalmerin acetate, a novel anticancer agent from Caribbean gorgonian octocorals, induces apoptosis in malignant glioma cells via the c-Jun NH2-terminal kinase pathway Mol. Cancer Ther., January 1, 2007; 6(1): 184 - 192. [Abstract] [Full Text] [PDF]

				M. Ogata, S.-i. Hino, A. Saito, K. Morikawa, S. Kondo, S. Kanemoto, T. Murakami, M. Taniguchi, I. Tanii, K. Yoshinaga, et al. Autophagy Is Activated for Cell Survival after Endoplasmic Reticulum Stress Mol. Cell. Biol., December 15, 2006; 26(24): 9220 - 9231. [Abstract] [Full Text] [PDF]

				C. Cao, T. Subhawong, J. M. Albert, K. W. Kim, L. Geng, K. R. Sekhar, Y. J. Gi, and B. Lu Inhibition of Mammalian Target of Rapamycin or Apoptotic Pathway Induces Autophagy and Radiosensitizes PTEN Null Prostate Cancer Cells. Cancer Res., October 15, 2006; 66(20): 10040 - 10047. [Abstract] [Full Text] [PDF]

				A. Herman-Antosiewicz, D. E. Johnson, and S. V. Singh Sulforaphane Causes Autophagy to Inhibit Release of Cytochrome c and Apoptosis in Human Prostate Cancer Cells Cancer Res., June 1, 2006; 66(11): 5828 - 5835. [Abstract] [Full Text] [PDF]

				S. Bandyopadhyay, R. Zhan, Y. Wang, S. K. Pai, S. Hirota, S. Hosobe, Y. Takano, K. Saito, E. Furuta, M. Iiizumi, et al. Mechanism of Apoptosis Induced by the Inhibition of Fatty Acid Synthase in Breast Cancer Cells Cancer Res., June 1, 2006; 66(11): 5934 - 5940. [Abstract] [Full Text] [PDF]

				H. Ito, H. Aoki, F. Kuhnel, Y. Kondo, S. Kubicka, T. Wirth, E. Iwado, A. Iwamaru, K. Fujiwara, K. R. Hess, et al. Autophagic cell death of malignant glioma cells induced by a conditionally replicating adenovirus. J Natl Cancer Inst, May 3, 2006; 98(9): 625 - 636. [Abstract] [Full Text] [PDF]

				G. Lavieu, F. Scarlatti, G. Sala, S. Carpentier, T. Levade, R. Ghidoni, J. Botti, and P. Codogno Regulation of Autophagy by Sphingosine Kinase 1 and Its Role in Cell Survival during Nutrient Starvation J. Biol. Chem., March 31, 2006; 281(13): 8518 - 8527. [Abstract] [Full Text] [PDF]

				S. Paglin, N.-Y. Lee, C. Nakar, M. Fitzgerald, J. Plotkin, B. Deuel, N. Hackett, M. McMahill, E. Sphicas, N. Lampen, et al. Rapamycin-Sensitive Pathway Regulates Mitochondrial Membrane Potential, Autophagy, and Survival in Irradiated MCF-7 Cells Cancer Res., December 1, 2005; 65(23): 11061 - 11070. [Abstract] [Full Text] [PDF]

				A. Terman and U. T. Brunk Autophagy in cardiac myocyte homeostasis, aging, and pathology Cardiovasc Res, December 1, 2005; 68(3): 355 - 365. [Abstract] [Full Text] [PDF]

				R.-A. Gonzalez-Polo, P. Boya, A.-L. Pauleau, A. Jalil, N. Larochette, S. Souquere, E.-L. Eskelinen, G. Pierron, P. Saftig, and G. Kroemer The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death J. Cell Sci., July 15, 2005; 118(14): 3091 - 3102. [Abstract] [Full Text] [PDF]

				S. Daido, A. Yamamoto, K. Fujiwara, R. Sawaya, S. Kondo, and Y. Kondo Inhibition of the DNA-Dependent Protein Kinase Catalytic Subunit Radiosensitizes Malignant Glioma Cells by Inducing Autophagy Cancer Res., May 15, 2005; 65(10): 4368 - 4375. [Abstract] [Full Text] [PDF]

				I. Papandreou, C. Krishna, F. Kaper, D. Cai, A. J. Giaccia, and N. C. Denko Anoxia Is Necessary for Tumor Cell Toxicity Caused by a Low-Oxygen Environment Cancer Res., April 15, 2005; 65(8): 3171 - 3178. [Abstract] [Full Text] [PDF]